Energetic modulation of nerves

ABSTRACT

A system to modulate an autonomic nerve in a patient utilizing transcutaneous ultrasound energy delivery includes a processor comprising an input for receiving information regarding energy and power to be delivered to a treatment region containing the nerve, and an output for outputting a signal, wherein the processor is configured to determine a position of a reference target from outside the patient to localize the nerve relative to the reference target, a therapeutic energy device comprising a transducer for delivering ultrasound energy from outside the patient, a controller to control an aiming of the transducer based at least in part on the signal from the processor, and an imaging system coupled to the processor or the therapeutic energy device.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.12/902,133, filed Oct. 11, 2010, pending, which claims priority to andthe benefit of U.S. Provisional patent application 61/377,908 filed Aug.27, 2010, now lapsed, and U.S. Provisional patent application 61/347,375filed May 21, 2010, now lapsed, and is a continuation-in-part of U.S.patent application Ser. No. 12/725,450 filed Mar. 16, 2010, now pending,which is a continuation-in-part of U.S. patent application Ser. No.12/685,655, filed on Jan. 11, 2010, now pending, which claims priorityto and the benefit of U.S. Provisional Patent Application No. 61/256,983filed Oct. 31, 2009, now lapsed, U.S. Provisional Patent Application No.61/250,857 filed Oct. 12, 2009, now lapsed, U.S. Provisional PatentApplication No. 61/261,741 filed Nov. 16, 2009, now lapsed, and U.S.Provisional Patent Application No. 61/291,359 filed Dec. 30, 2009, nowlapsed.

U.S. patent application Ser. No. 12/725,450 also claims priority to, andthe benefit of U.S. Provisional Patent Application No. 61/303,307 filedFeb. 10, 2010, now lapsed, U.S. Provisional Patent Application No.61/256,983 filed Oct. 31, 2009, now lapsed, U.S. Provisional PatentApplication No. 61/250,857 filed Oct. 12, 2009, now lapsed, U.S.Provisional Patent Application No. 61/261,741 filed Nov. 16, 2009, nowlapsed, and U.S. Provisional Patent Application No. 61/291,359 filedDec. 30, 2009, now lapsed.

The disclosures of all of the above referenced applications areexpressly incorporated by reference herein.

The following patent applications are also expressly incorporated byreference herein.

U.S. patent application Ser. Nos. 11/583,569, 12/762,938, 11/583,656,12/247,969, 10/633,726, 09/721,526, 10/780,405, 09/747,310, 12/202,195,11/619,996, 09/696,076, 11/016,701, 12/887,178, 12/390,975, 12/887,178,12/887,211, 12/887,232

It should be noted that the subject matters of the above applicationsand any other applications referenced herein are expressly incorporatedinto this application as if they are expressly recited in thisapplication. Thus, in the instance where the references are notspecifically labeled as “incorporated by reference” in this application,they are in fact deemed described in this application.

BACKGROUND

Energy delivery from a distance involves transmission of energy waves toaffect a target at a distance. It allows for more efficient delivery ofenergy to targets and a greater cost efficiency and technologicflexibility on the generating side. For example, cellular phones receivetargets from towers close to the user and the towers communicate withone another over a long range; this way, the cell phones can be lowpowered and communicate over a relatively small range yet the networkcan quickly communicate across the world. Similarly, electricitydistribution from large generation stations to the users is moreefficient than the users themselves looking for solutions.

In terms of treating a patient, delivering energy over a distanceaffords great advantages as far as targeting accuracy, technologicflexibility, and importantly, limited invasiveness into the patient. Ina simple form, laparoscopic surgery has replaced much of the previousopen surgical procedures and lead to creation of new procedures anddevices as well as a more efficient procedural flow for diseasetreatment. Laparoscopic tools deliver the surgeon's energy to thetissues of the patient from a distance and results in improved imagingof the region being treated as well as the ability for many surgeons tovisualize the region at the same time.

Perhaps the most important aspect is the fact that patients have muchless pain, fewer complications, and the overall costs of the proceduresare lower. Visualization is improved as is the ability to perform tasksrelative to the visualization.

Continued advances in computing, miniaturization and economization ofenergy delivery technologies, and improved imaging will lead to stillgreater opportunities to apply energy from a distance into the patientand treat disease.

SUMMARY

In some embodiments, a system to modulate an autonomic nerve in apatient utilizing transcutaneous ultrasound energy delivery includes aprocessor comprising an input for receiving information regarding energyand power to be delivered to a treatment region containing the nerve,and an output for outputting a signal, wherein the processor isconfigured to determine a position of a reference target from outsidethe patient to localize the nerve relative to the reference target, atherapeutic energy device comprising a transducer for deliveringultrasound energy from outside the patient, a controller to control anaiming of the transducer based at least in part on the signal from theprocessor, and an imaging system coupled to the processor or thetherapeutic energy device.

In other embodiments, a system to inhibit a function of a nervesurrounding a renal artery includes a detector to detect a positionalsignal indicative of a location of the renal artery from a positionexternal to a patient, an ultrasound component to deliver therapeuticenergy through a skin of the patient to the nerve surrounding the renalartery, and a processing unit configured to obtain information regardinga three dimensional coordinate space containing the ultrasoundcomponent, obtain the location of the renal artery, and determine adirection and an energy level for the therapeutic energy based on theinformation and the location of the renal artery.

In other embodiments, a method to stimulate or inhibit the function of anerve traveling to or from the kidney includes identifying an acousticwindow at the posterior region of a patient in which renal arteries canbe visualized, transmitting a first energy through a skin of the patientfrom the posterior region of the patient, imaging an arterial regionusing the first transmitted energy, and applying a second transmittedenergy to an arterial adventitia based on the imaged arterial region.

In other embodiments, a method to locate a position of a blood vessel ina body of a patient includes applying a first wave of ultrasound, from afirst direction, to a region of a blood vessel from outside of thepatient, and detecting its return signal, comparing the applied firstwave and its return signal, simultaneously, or sequentially, applying asecond wave of ultrasound from a second direction to the blood vessel,and detecting a its return signal, and integrating the return signalfrom the first wave and the return signal from the second wave todetermine the position, in a three dimensional coordinate reference, ofthe blood vessel.

In some embodiments, procedures and devices are provided, which advancethe art of medical procedures involving transmitted energy to treatdisease. The procedures and devices follow along the lines of: 1)transmitting energy to produce an effect in a patient from a distance;2) allowing for improved imaging or targeting at the site of treatment;3) creating efficiencies through utilization of larger and more powerfuldevices from a position of distance from or within the patient asopposed to attempting to be directly in contact with the target as asurgeon, interventional cardiologist or radiologist might do. In manycases, advanced visualization and localization tools are utilized aswell.

In some embodiments, a method of treatment includes placing an energysource outside a patient, operating the energy source so that an energydelivery path of the energy source is aimed towards a nerve inside thepatient, wherein the nerve is a part of an autonomic nervous system, andusing the energy source to deliver treatment energy from outside thepatient to the nerve located inside the patient to treat the nerve.

In some embodiments, the treatment energy comprises focused energy.

In some embodiments, the treatment energy comprises non-focused energy.

In some embodiments, the treatment energy comprises HIFU energy.

In some embodiments, the treatment energy comprises LIFU energy.

In some embodiments, the treatment energy is delivered to the nerve toachieve partial ablation of the nerve.

In some embodiments, the treatment energy is delivered to the nerve toachieve complete ablation of the nerve.

In some embodiments, the treatment energy is delivered to achieveparalysis of the nerve.

In some embodiments, the nerve leads to a kidney.

In some embodiments, the nerve comprises a renal nerve.

In some embodiments, the nerve comprises a sympathetic nerve connectedto the kidney.

In some embodiments, the nerve comprises an afferent nerve connected tothe kidney.

In some embodiments, the nerve comprises a renal sympathetic nerve at arenal pedicle.

In some embodiments, the nerve comprises a nerve trunk adjacent to avertebra.

In some embodiments, the nerve comprises a ganglion adjacent to avertebra.

In some embodiments, the nerve comprises a dorsal root nerve.

In some embodiments, the nerve leads to an adrenal gland.

In some embodiments, the nerve comprises a motor nerve.

In some embodiments, the nerve is next to a kidney.

In some embodiments, the nerve is behind an eye.

In some embodiments, the nerve comprises a celiac plexus.

In some embodiments, the nerve is within or around a vertebral column.

In some embodiments, the nerve extends to a facet joint

In some embodiments, the nerve comprises a celiac ganglion.

In some embodiments, the act of operating the energy source comprisespositioning the energy source.

In some embodiments, the energy source comprises an ultrasound energysource.

In some embodiments, the ultrasound energy source is used to deliver thetreatment energy to the nerve from multiple directions outside thepatient.

In some embodiments, the treatment energy is delivered to modulate thenerve without damaging the nerve.

In some embodiments, the method further includes determining a positionof a renal vessel using an imaging device located outside the patient.

In some embodiments, the position of the renal vessel is used todetermine a position of the nerve.

In some embodiments, the imaging device comprises a CT device, an MRIdevice, a thermography device, an infrared imaging device, an opticalcoherence tomography device, a photoacoustic imaging device, a PETimaging device, a SPECT imaging device, or an ultrasound device.

In some embodiments, the method further includes determining a positionof the nerve inside the patient.

In some embodiments, the act of determining the position of the nerveinside the patient comprises determining a position of a renal vessel totarget the nerve that surrounds the renal vessel.

In some embodiments, the renal vessel comprises a renal artery.

In some embodiments, the act of determining the position of the nerveinside the patient comprises using a Doppler triangulation technique.

In some embodiments, the imaging device comprises a MRI device.

In some embodiments, the imaging device comprises a CT device.

In some embodiments, the treatment energy comprises HIFU energy, and theimaging device comprises a MRI device.

In some embodiments, the treatment energy comprises HIFU energy, and theimaging device comprises an ultrasound device.

In some embodiments, the nerve leads to a kidney, and the imaging devicecomprises a MRI device.

In some embodiments, the nerve leads to a kidney, and the imaging devicecomprises an ultrasound device.

In some embodiments, the nerve leads to a kidney, and the imaging deviceis used to obtain a doppler signal.

In some embodiments, the treatment energy is delivered to a kidney todecrease a sympathetic stimulus to the kidney, decrease an afferentsignal from the kidney to an autonomic nervous system, or both.

In some embodiments, the method further includes delivering testingenergy to the patient to determine if there is a reaction resultedtherefrom, wherein the testing energy is delivered before the treatmentenergy is delivered from the energy source.

In some embodiments, the testing energy comprises heat or vibratoryenergy, and the method further comprises performing a test to detectsympathetic nerve activity.

In some embodiments, the testing energy comprises a stimulus applied toa skin, and the method further comprises detecting an output from thepatient.

In some embodiments, the output comprises a heart rate.

In some embodiments, the test energy is delivered to stimulate abaroreceptor complex, and the method further includes applying pressureto a carotid artery, and determining whether a blood pressure decreasesafter application of the pressure to the carotid artery.

In some embodiments, the test energy is delivered using an ultrasounddevice that is placed outside the patient.

In some embodiments, the treatment energy from the energy source isdelivered if the blood pressure decreases or if the blood pressuredecreases at a rate that is above a prescribed threshold.

In some embodiments, the treatment energy is delivered to treathypertension.

In some embodiments, the treatment energy is delivered to treatglaucoma.

In some embodiments, the energy source is operated so that the energysource aims at a direction that aligns with a vessel that is next to thenerve.

In some embodiments, the method further includes tracking a movement ofa treatment region containing the nerve.

In some embodiments, the energy delivery path of the energy source isaimed towards the nerve by using a position of a blood vessel that issurrounded by the nerve.

In some embodiments, the method further includes delivering a deviceinside the patient, and using the device to determine a position of thenerve inside the patient, wherein the energy source is operated based atleast in part on the determined position so that the energy deliverypath is aimed towards the nerve.

In some embodiments, the device is placed inside a vessel that issurrounded by the nerve, and the position of the nerve is determinedindirectly by determining a position of the vessel.

In some embodiments, a system for treatment includes an energy sourcefor placement outside a patient, wherein the energy source is configuredto aim an energy delivery path towards a nerve that is a part of anautonomic nervous system inside the patient, and wherein the energysource is configured to deliver treatment energy from outside thepatient to the nerve located inside the patient to treat the nerve.

In some embodiments, the energy source is configured to provide focusedenergy.

In some embodiments, the energy source is configured to providenon-focused energy.

In some embodiments, the energy source is configured to provide HIFUenergy.

In some embodiments, the energy source is configured to provide LIFUenergy.

In some embodiments, the energy source is configured to provide thetreatment energy to achieve partial ablation of the nerve.

In some embodiments, the energy source is configured to deliver thetreatment energy to achieve complete ablation of the nerve.

In some embodiments, the energy source is configured to deliver thetreatment energy to achieve paralysis of the nerve.

In some embodiments, the energy source comprises an ultrasound energysource.

In some embodiments, the ultrasound energy source is configured todeliver the treatment energy to the nerve from multiple directionsoutside the patient while the ultrasound energy source is stationaryrelative to the patient.

In some embodiments, the energy source is configured to deliver thetreatment energy to modulate the nerve without damaging tissues that arewithin a path of the treatment energy to the nerve.

In some embodiments, the nerve comprises a renal nerve, and the systemfurther includes a processor located outside the patient, wherein theprocessor is configured for receiving an input related to a position ofa renal artery, determining an output related to a position of the renalnerve based on a model that associates artery position with nerveposition, and providing the output to a positioning system for theenergy source so that the positioning system can cause the energy sourceto deliver the treatment energy from the outside of the patient to therenal nerve to treat the renal nerve.

In some embodiments, the system further includes a processor fordetermining a position of a renal vessel located outside the patient.

In some embodiments, the system further includes an imaging device forproviding an image signal, wherein the processor is configured todetermine the position based on the image signal.

In some embodiments, the imaging device comprises a CT device, a MRIdevice, a thermography device, an infrared imaging device, an opticalcoherence tomography device, a photoacoustic imaging device, a PETimaging device, a SPECT imaging device, or an ultrasound device.

In some embodiments, the position of the renal vessel is used during thetreatment energy delivery to target the nerve that surrounds the renalvessel.

In some embodiments, the position is determined using a Dopplertriangulation technique.

In some embodiments, the renal vessel comprises a renal artery.

In some embodiments, treatment energy is delivered to a kidney todecrease a sympathetic stimulus to the kidney, decrease an afferentsignal from the kidney to an autonomic nervous system, or both.

In some embodiments, the energy source is also configured to delivertesting energy to the patient to determine if there is a reactionresulted therefrom.

In some embodiments, the energy source is configured to deliver thetreatment energy to treat hypertension.

In some embodiments, the energy source is configured to deliver thetreatment energy to treat glaucoma.

In some embodiments, the energy source has an orientation so that theenergy source aims at a direction that aligns with a vessel that is nextto the nerve.

In some embodiments, the energy source is configured to track a movementof the nerve.

In some embodiments, the energy source is configured to track themovement of the nerve by tracking a movement of a blood vessel next tothe nerve.

In some embodiments, the energy source is configured to aim at the nerveby aiming at a vessel that is surrounded by the nerve.

In some embodiments, the system further includes a device for placementinside the patient, and a processor for determining a position using thedevice, wherein the energy source is configured to aim the energydelivery path towards the nerve inside the patient based at least inpart on the determined position.

In some embodiments, the device is sized for insertion into a vesselthat is surrounded by the nerve.

In some embodiments, a system to deliver energy from a position outsidea skin of a patient to a nerve surrounding a blood vessel inside thepatient, includes a processor configured to receive image signal, anddetermine a three dimensional coordinate of a blood vessel based on theimage signal, and an energy source configured to deliver energy from theposition outside the skin of the patient to the nerve surrounding theblood vessel, wherein the processor is also configured to control theenergy source based on the determined coordinate.

In some embodiments, the system further includes an imaging device forproviding the image signal.

In some embodiments, the imaging device comprises a MRI device.

In some embodiments, the imaging device comprises an ultrasound device.

In some embodiments, the energy comprises focused energy.

In some embodiments, the energy comprises focused ultrasound.

In some embodiments, the energy source comprises an ultrasound arraythat is aligned with the vessel.

In some embodiments, the system further includes an imaging device forproviding a B-mode ultrasound for imaging the blood vessel.

In some embodiments, a system to deliver energy from a position outsidea skin of a patient to a nerve surrounding a blood vessel includes afiducial for placement inside the blood vessel, a detection device todetect the fiducial inside the blood vessel, a processor configured todetermine a three dimensional coordinate of the detected fiducial, andan energy source configured to transmit energy through the skin and tofocus the energy at the region of the blood vessel, wherein theprocessor is configured to operate the energy source based on thedetermined three dimensional coordinate of the fiducial, and informationregarding the blood vessel.

In some embodiments, the energy source comprises an ultrasound device,and wherein the blood vessel is a renal artery.

In some embodiments, the system further includes an ultrasound imagingsystem.

In some embodiments, the fiducial is placed inside the blood vessel andis attached to an intravascular catheter.

In some embodiments, the fiducial is a passive fidicial that isconfigured to respond to an external signal.

In some embodiments, the fiducial is an active fiducial, transmittingits position to the detection device.

In some embodiments, a method to treat hypertension in a patientincludes obtaining an imaging signal from a blood vessel in the patient,planning a delivery of energy to a wall of the blood vessel, anddelivering energy from outside a skin of the patient to an autonomicnerve surrounding the blood vessel.

In some embodiments, the method further includes selectively modulatingan afferent nerve within a sympathetic nerve bundle.

In some embodiments, the method further includes utilizingmicroneurography after the delivery of the energy to determine an effectof the energy delivery on a sympathetic nervous system.

In some embodiments, the blood vessel extends to or from a kidney, andthe method further comprises locating the blood vessel with dopplerultrasound.

In some embodiments, a system to modulate an autonomic nerve in apatient utilizing transcutaneous energy delivery, the system includes aprocessor comprising an input for receiving information regarding energyand power to be delivered to a treatment region containing the nerve,and an output for outputting a signal, wherein the processor isconfigured to determine a position of a reference target from outsidethe patient to localize the nerve relative to the reference target, atherapeutic energy device comprising a transducer for delivering energyfrom outside the patient, a controller to control an aiming of thetransducer based at least in part on the signal from the processor, andan imaging system coupled to the processor or the therapeutic energydevice.

In some embodiments, the processor is configured to determine theposition during an operation of the therapeutic energy device.

In some embodiments, the system further includes a patient interfaceconfigured to position the therapeutic device so that the transducer isaimed toward a blood vessel connected to a kidney from a positionbetween ribs superiorly, a iliac crest inferiorly, and a vertebralcolumn medially.

In some embodiments, the therapeutic energy device is configured todeliver focused ultrasound.

In some embodiments, the reference target is at least a portion of ablood vessel traveling to or from a kidney, and the nerve is a renalnerve.

In some embodiments, the transducer is configured to focus energy at adistance from 6 cm to 18 cm.

In some embodiments, the transducer is configured to deliver the energyin a form of focused ultrasound to a renal blood vessel at an angleranging between about −10 degrees and about −48 degrees relative to ahorizontal line connecting transverse processes of a spinal column.

In some embodiments, the energy from the therapeutic energy deviceranges between 100 W/cm2 and 2500 W/cm2.

In some embodiments, the reference target is an indwelling vascularcatheter.

In some embodiments, the imaging system is a magnetic resonance imagingsystem and the therapeutic energy device is an ultrasound device.

In some embodiments, the imaging system is an ultrasound imaging system.

In some embodiments, the processor is a part of the therapeutic energydevice.

In some embodiments, the processor is a part of the imaging system.

In some embodiments, a method to deliver energy from a position outsidethe skin of a patient to a nerve surrounding a blood vessel, includesplacing a device inferior to ribs, superior to an iliac crest, andlateral to a spine, and using the device to maintain an energy deliverysystem at a desired position relative to the patient so that the energydelivery system can deliver energy through the skin without traversingbone.

In some embodiments, the energy delivery system comprises a focusedultrasound delivery system.

In some embodiments, a device for use in a system to deliver focusedultrasound energy from a position outside a skin of a patient to a nervesurrounding a blood vessel, includes a positioning device configured tomaintain an energy delivery system at a desired position relative to thepatient so that the energy delivery system can deliver energy throughthe skin without traversing bone, wherein the positioning device isconfigured to be placed inferior to ribs, superior to an iliac crest,and lateral to a spine.

In some embodiments, the energy delivery system comprises a focusedultrasound delivery system.

In some embodiments, the positioning device is configured to maintain anangle of the focused ultrasound delivery system such that bonystructures are not include in an ultrasound field.

In some embodiments, a system for treatment includes a treatment deviceconfigured to deliver energy from outside a patient to a nerve insidethe patient, a catheter configured for placement inside a vesselsurrounded by the nerve, the catheter configured to transmit a signal,and a processor configured to receive the signal and determine areference position in the vessel, wherein the treatment device isconfigured deliver the energy to the nerve based on the determinedreference position.

In some embodiments, the treatment device comprises an ultrasounddevice.

In some embodiments, a method of inhibiting the function of a nervetraveling with an artery includes providing an external imaging modalityto determine the location of the artery of a patient, placing the arteryin a first three dimensional coordinate reference based on the imaging,placing or associating a therapeutic energy generation source in thefirst three dimensional coordinate reference frame, modeling thedelivery of energy to the adventitial region of the artery or a regionadjacent to the artery where a nerve travels, delivering therapeuticenergy from the therapeutic energy source, from at least two differentangles, through the skin of a patient, to intersect at the artery or theregion adjacent to the artery, and at least partially inhibiting thefunction of the nerve traveling with the artery.

In some embodiments, the imaging modality is one of: ultrasound, MRI,and CT.

In some embodiments, the therapeutic energy is ultrasound.

In some embodiments, the artery is a renal artery.

In some embodiments, placing the artery in a three dimensional referenceframe comprises locating the artery using a doppler ultrasound signal.

In some embodiments, the method further includes utilizing a fiducialwherein the fiducial is placed internal to the patient.

In some embodiments, said fiducial is temporarily placed in a positioninternal to the patient.

In some embodiments, said fiducial is a catheter placed in the artery ofthe patient.

In some embodiments, said catheter is detectable using a radiofrequencysignal and said imaging modality is ultrasound.

In some embodiments, the therapeutic energy from the energy source isdelivered in a distribution along the length of the artery.

In some embodiments, the therapeutic energy is ionizing radiation.

In some embodiments, a system to inhibit the function of a nervetraveling with a renal artery includes a detector to determine thelocation of the renal artery and renal nerve from a position external toa patient, an ultrasound component to deliver therapeutic energy throughthe skin from at least two directions to the nerve surrounding the renalartery, a modeling algorithm comprising an input and an output, saidinput to the modeling algorithm comprising a three dimensionalcoordinate space containing a therapeutic energy source and the positionof the renal artery in the three dimensional coordinate space, and saidoutput from the modeling algorithm comprising the direction and energylevel of the ultrasound component, a fiducial, locatable from a positionoutside a patient, adapted to be temporarily placed in the artery of thepatient and communicate with the detector to determine the location ofthe renal artery in a three dimensional reference frame, the informationregarding the location transmittable as the input to the model.

In some embodiments, the fiducial is a passive reflector of ultrasound.

In some embodiments, the fiducial generates radiofrequency energy.

In some embodiments, the fiducial is activated to transmit energy basedon a signal from an ultrasound or magnetic field generator.

In some embodiments, the output from the model instructs the ultrasoundcomponent to deliver a lesion on the artery in which the major axis ofthe lesion is longitudinal along the length of the artery.

In some embodiments, the output from the model instructs the ultrasoundcomponent to deliver multiple lesions around an artery simultaneously.

In some embodiments, the output from the model instructs the ultrasoundcomponent to deliver a circumferential lesion around the artery.

In some embodiments, the lesion is placed around the renal artery justproximal to the bifurcation of the artery in the hilum of the kidney.

In some embodiments, a method to stimulate or inhibit the function of anerve traveling to or from the kidney includes identifying an acousticwindow at the posterior region of a patient in which the renal arteriescan be visualized, transmitting a first energy through the skin of apatient from the posterior region of the patient, imaging an arterialregion using the first transmitted energy, and applying a secondtransmitted energy to the arterial adventitia by coupling the imagingand the second transmitted energy.

In some embodiments, the method further includes tracking the imagecreated by the first transmitted energy.

In some embodiments, a method to locate the position of a blood vesselin the body of a patient includes applying a first wave of ultrasound,from a first direction, to a region of a blood vessel from outside ofthe patient and detecting its return signal, comparing the applied firstwave and its return signal, simultaneously, or sequentially, applying asecond wave of ultrasound from a second direction to the blood vesseland detecting a its return signal, and integrating the return signalsfrom the first wave and the return signals from the second wave todetermine the position, in a three dimensional coordinate reference, ofthe blood vessel.

In some embodiments, the method further includes the step of instructinga therapeutic ultrasound transducer to apply energy to the position ofthe blood vessel.

DESCRIPTION OF FIGURES

FIGS. 1 a-b depict the focusing of energy sources on nerves of theautonomic nervous system.

FIG. 1 c depicts an imaging system to help direct the energy sources.

FIG. 2 depicts targeting and/or therapeutic ultrasound delivered throughthe stomach to the autonomic nervous system posterior to the stomach.

FIG. 3 a depicts focusing of energy waves on the renal nerves.

FIG. 3 b depicts a coordinate reference frame for the treatment.

FIG. 3C depicts targeting catheters placed in any of the renal vessels.

FIG. 3D depicts an image detection system of a blood vessel with atemporary fiducial placed inside.

FIG. 3E depicts a therapy paradigm for the treatment and assessment ofhypertension.

FIG. 4 a depicts the application of energy to the autonomic nervoussystem surrounding the carotid arteries.

FIG. 4B depicts the application of energy to through the vessels of therenal hilum.

FIGS. 5 a-b depicts the application of focused energy to the autonomicnervous system of the eye.

FIG. 6 depicts the application of constricting lesions to the kidneydeep inside the calyces of the kidney.

FIG. 7 a depicts a patient in an imaging system receiving treatment withfocused energy waves.

FIG. 7 b depicts visualization of a kidney being treated.

FIG. 7 c depicts a close up view of the renal nerve region of the kidneybeing treated.

FIG. 7 d depicts an algorithmic method to treat the autonomic nervoussystem using MRI and energy transducers.

FIG. 7 e depicts a geometric model obtained from cross-sectional imagesof the area of the aorta and kidneys.

FIG. 7F depicts a close up image of the region of treatment.

FIG. 7G depicts the results of measurements from a series of crosssectional image reconstructions.

FIG. 7H depicts the results of measurements from a series ofcross-sectional images from a patient in a more optimized position.

FIG. 7I depicts an algorithmic methodology to apply treatment to thehilum of the kidney and apply energy to the renal blood vessels.

FIG. 8 a depicts a percutaneous approach to treating the autonomicnervous system surrounding the kidneys.

FIG. 8 b depicts an intravascular approach to treating or targeting theautonomic nervous system.

FIG. 8C depicts a percutaneous approach to the renal hila using a CTscan and a probe to reach the renal blood vessels.

FIGS. 9 a-c depicts the application of energy from inside the aorta toregions outside the aorta to treat the autonomic nervous system.

FIG. 10 depicts steps to treat a disease using HIFU while monitoringprogress of the treatment as well as motion.

FIG. 11 a depicts treatment of brain pathology using cross sectionalimaging.

FIG. 11 b depicts an image on a viewer showing therapy of the region ofthe brain being treated.

FIG. 11 c depicts another view of a brain lesion as might be seen on animaging device which assists in the treatment of the lesion.

FIG. 12 depicts treatment of the renal nerve region using a laparoscopicapproach.

FIG. 13 depicts a methodology for destroying a region of tissue usingimaging markers to monitor treatment progress.

FIG. 14 depicts the partial treatment of portions of a nerve bundleusing converging imaging and therapy wave.

FIG. 15 a-b depicts the application of focused energy to the vertebralcolumn to treat various spinal pathologies including therapy of thespinal or intravertebral nerves.

FIG. 16A depicts the types of lesions which are created around the renalarteries to affect a response.

FIG. 16B depicts a simulation of ultrasound around a blood vessel Isupport of FIG. 16A.

FIG. 16C depicts data from ultrasound energy applied to the renal bloodvessels and the resultant change in norepinephrine levels.

FIG. 17A depicts the application of multiple transducers to treatregions of the autonomic nervous system at the renal hilum.

FIGS. 17B-C depict methods for using imaging to direct treatment of aspecific region surrounding an artery as well as display the predictedlesion morphology.

FIG. 17D depicts a method for localizing HIFU transducers relative toDoppler ultrasound signals.

FIG. 17E depicts an arrangement of transducers relative to a target.

FIG. 17F depicts ablation zones in a multi-focal region incross-section.

FIG. 18 depicts the application of energy internally within the kidneyto affect specific functional changes at the regional level within thekidney.

FIG. 19A depicts the direction of energy wave propagation to treatregions of the autonomic nervous system around the region of the kidneyhilum.

FIG. 19B depicts a schematic of a B mode ultrasound from a directiondetermined through experimentation to provide access to the renal hilumwith HIFU.

FIG. 20 depicts the application of ultrasound waves through the wall ofthe aorta to apply a therapy to the autonomic nervous system.

FIG. 21A depicts application of focused energy to the ciliary musclesand processes of the anterior region of the eye.

FIG. 21B depicts the application of focused non-ablative energy to theback of the eye to enhance drug or gene delivery or another therapy suchas ionizing radiation.

FIG. 22 depicts the application of focused energy to nerves surroundingthe knee joint to affect nerve function in the joint.

FIGS. 23A-B depicts the application of energy to the fallopian tube tosterilize a patient.

FIG. 24 depicts an algorithm to assess the effect of the neuralmodulation procedure on the autonomic nervous system. After a procedureis performed on the renal nerves, assessment of the autonomic responseis performed by, for example, simulating the autonomic nervous system inone or more places.

FIG. 25 depicts an optimized position of a device to apply therapy tointernal nerves.

FIG. 26A depicts positioning of a patient to obtain parameters forsystem design.

FIG. 26B depicts a device design based on the information learned fromfeasibility studies.

FIG. 27 depicts a clinical paradigm for treating the renal nerves of theautonomic nervous system based on feasibility studies.

FIG. 28 A-C depicts a treatment positioning system for a patientincorporating a focused ultrasound system.

FIG. 29 A-D depicts results of studies applying focused energy to nervessurrounding arteries and of ultrasound studies to visualize the bloodvessels around which the nerves travel.

FIG. 29E depicts the results of design processes in which the angle,length, and surface area from CT scans is quantified.

FIGS. 30A-I depicts results of simulations to apply focused ultrasoundto the region of a renal artery with a prototype device design based onsimulations.

DETAILED DESCRIPTION

Hypertension is a disease of extreme national and internationalimportance. There are 80 million patients in the US alone who havehypertension and over 200 million in developed countries worldwide. Inthe United States, there are 60 million patients who have uncontrolledhypertension, meaning that they are either non-compliant or cannot takethe medications because of the side effect profile. Up to 10 millionpeople might have completely resistant hypertension in which they do notreach target levels no matter what the medication regimen. Themorbidities associated with uncontrolled hypertension are profound,including stroke, heart attack, kidney failure, peripheral arterialdisease, etc. A convenient and straightforward minimally invasiveprocedure to treat hypertension would be a very welcome advance in thetreatment of this disease.

Congestive Heart Failure (“CHF”) is a condition which occurs when theheart becomes damaged and blood flow is reduced to the organs of thebody. If blood flow decreases sufficiently, kidney function becomesaltered, which results in fluid retention, abnormal hormone secretionsand increased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.For example, as the heart struggles to pump blood, the cardiac output ismaintained or decreased and the kidneys conserve fluid and electrolytesto maintain the stroke volume of the heart. The resulting increase inpressure further overloads the cardiac muscle such that the cardiacmuscle has to work harder to pump against a higher pressure. The alreadydamaged cardiac muscle is then further stressed and damaged by theincreased pressure. Moreover, the fluid overload and associated clinicalsymptoms resulting from these physiologic changes result in additionalhospital admissions, poor quality of life, and additional costs to thehealth care system. In addition to exacerbating heart failure, kidneyfailure can lead to a downward spiral and further worsening kidneyfunction. For example, in the forward flow heart failure describedabove, (systolic heart failure) the kidney becomes ischemic. In backwardheart failure (diastolic heart failure), the kidneys become congestedvis-à-vis renal vein hypertension. Therefore, the kidney can contributeto its own worsening failure.

The functions of the kidneys can be summarized under three broadcategories: filtering blood and excreting waste products generated bythe body's metabolism; regulating salt, water, electrolyte and acid-basebalance; and secreting hormones to maintain vital organ blood flow.Without properly functioning kidneys, a patient will suffer waterretention, reduced urine flow and an accumulation of waste toxins in theblood and body. These conditions result from reduced renal function orrenal failure (kidney failure) and are believed to increase the workloadof the heart. In a CHF patient, renal failure will cause the heart tofurther deteriorate as fluids are retained and blood toxins accumulatedue to the poorly functioning kidneys. The resulting hypertension alsohas dramatic influence on the progression of cerebrovascular disease andstroke.

The autonomic nervous system is a network of nerves which affect almostevery organ and physiologic system to a variable degree. Generally, thesystem is composed of sympathetic and parasympathetic nerves. Forexample, the sympathetic nerves to the kidney traverse the sympatheticchain along the spine and synapse within the ganglia of the chain orwithin the celiac ganglia, then proceeding to innervate the kidney viapost-ganglionic fibers inside the “renal nerves.” Within the renalnerves, which travel along the renal hila (artery and to some extent thevein), are the post-ganglionic sympathetic nerves and the afferentnerves from the kidney. The afferent nerves from the kidney travelwithin the dorsal root (if they are pain fibers) and into the anteriorroot if they are sensory fibers, then into the spinal cord andultimately to specialized regions of the brain. The afferent nerves,baroreceptors and chemoreceptors, deliver information from the kidneysback to the sympathetic nervous system via the brain; their ablation orinhibition is at least partially responsible for the improvement seen inblood pressure after renal nerve ablation, or denervation, or partialdisruption. It has also been suggested and partially provenexperimentally that the baroreceptor response at the level of thecarotid sinus is mediated by the renal artery afferent nerves such thatloss of the renal artery afferent nerve response blunts the response ofthe carotid baroreceptors to changes in arterial blood pressure(American J. Physiology and Renal Physiology 279:F491-F501, 2000,incorporated by reference herein).

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads todecreased removal of water and sodium from the body, as well asincreased renin secretion which stimulates aldosterone secretion fromthe adrenal gland. Increased renin secretion can lead to an increase inangiotensin II levels which leads to vasoconstriction of blood vesselssupplying the kidneys as well as systemic vasoconstriction, all of whichlead to a decrease in renal blood flow and hypertension. Reduction insympathetic renal nerve activity, e.g., via de-innervation, may reversethese processes and in fact has been shown to in the clinic. Similarly,in obese patients, the sympathetic drive is intrinsically very high andis felt to be one of the causes of hypertension in obese patients.

Recent clinical work has shown that de-innervation of the renalsympathetic chain and other nerves which enter the kidney through thehilum can lead to profound systemic effects in patients (rats, dogs,pig, sheep, humans) with hypertension, heart failure, and other organsystem diseases. Such treatment can lead to long term reduction in theneed for blood pressure medications and improvements in blood pressure(O'Brien Lancet 2009 373; 9681 incorporated by reference). The devicesused in this trial were highly localized radiofrequency (RF) ablation toablate the renal artery adventitia with the presumption that the nervessurrounding the renal artery are being inhibited in the heating zone aswell. The procedure is performed in essentially a blind fashion in thatthe exact location of the nerve plexus is not known prior to, during, orafter the procedure. In addition, the wall of the renal artery isinvariably damaged by the RF probe and patients whose vessels have agreat deal of atherosclerosis cannot be treated safely. In addition,depending on the distance of the nerves from the vessel wall, the energymay not consistently lead to ablation or interruption. Finally, the useof internal catheters may not allow for treatment inside the kidney orinside the aorta if more selective. In many cases, it is required tocreate a spiral along the length and inside the blood vessel to avoidcircumferential damage to the vessel.

Cross-sectional imaging can be utilized to visualize the internalanatomy of patients via radiation (CT) or magnetic fields (MRI).Ultrasound can also be utilized to obtain cross-sections of specificregions but only at high frequencies; therefore, ultrasound is typicallylimited to imaging superficial body regions. CT and MRI are often moreamenable to cross sectional imaging because the radiation penetrateswell into tissues. In addition, the scale of the body regions ismaintained such that the anatomy within the coordinate referencesremains intact relative to one another; that is, distances betweenstructures can be measured.

With ultrasound, scaling can be more difficult because of unequalpenetration as the waves propagate deeper through the tissue. CT scansand MRIs and even ultrasound devices can be utilized to create threedimensional representations and reconstructed cross-sectional images ofpatients; anatomy can be placed in a coordinate reference frame using athree dimensional representation. Once in the reference frame, energydevices (transducers) can be placed in position and energy emittingdevices directed such that specific regions of the body are targeted.Once knowledge of the transducer position is known relative to theposition of the target in the patient body, energy can be delivered tothe target.

Ultrasound is a cyclically generated sound pressure wave with afrequency greater than the upper limit of human hearing . . . 20kilohertz (kHz). In medicine, ultrasound is widely utilized because ofits ability to penetrate tissues. Reflection of the sound waves revealsa signature of the underlying tissues and as such, ultrasound can beused extensively for diagnostics and potentially therapeutics as well inthe medical field. As a therapy, ultrasound has the ability to bothpenetrate tissues and can be focused to create ablation zones. Becauseof its simultaneous ability to image, ultrasound can be utilized forprecise targeting of lesions inside the body. Ultrasound intensity ismeasured by the power per cm² (for example, W/cm² at the therapeutictarget region). Generally, high intensity refers to intensities over0.1-5 kW/cm². Low intensity ultrasound encompasses the range up to0.01-0.10 kW/cm² from about 1 or 10 Watts per cm².

Ultrasound can be utilized for its forward propagating waves andresulting reflected waves or where energy deposition in the tissue andeither heating or slight disruption of the tissues is desired. Forexample, rather than relying on reflections for imaging, lower frequencyultrasonic beams (e.g. <1 MHz) can be focused at a depth within tissue,creating a heating zone or a defined region of cavitation in whichmicro-bubbles are created, cell membranes are opened to admit bioactivemolecules, or damage is otherwise created in the tissue. These featuresof ultrasound generally utilize frequencies in the 0.25 Megahertz (MHz)to 10 MHz range depending on the depth required for effect. Focusing is,or may be, required so that the surface of the tissue is not excessivelyinjured or heated by single beams. In other words, many single beams canbe propagated through the tissue at different angles to decrease theenergy deposition along any single path yet allow the beams to convergeat a focal spot deep within the tissue. In addition, reflected beamsfrom multiple angles may be utilized in order to create a threedimensional representation of the region to be treated in a coordinatespace.

It is important when planning an ultrasound therapy that sharp,discontinuous interfaces be avoided. For example, bowel, lung, bonewhich contain air and/or bone interfaces constitute sharp boundarieswith soft tissues. These interfaces make the planning and therapy moredifficult. If however, the interfaces can be avoided, then treatment canbe greatly simplified versus what has to done for the brain (e.g.MR-guided HIFU) where complex modeling is required to overcome the veryhigh attenuation of the cranium. Data provided below reveals a discoverythrough extensive experimentation as to how to achieve this treatmentsimplicity.

Time of flight measurements with ultrasound can be used to range find,or find distances between objects in tissues. Such measurements can beutilized to place objects such as vessels into three dimensionalcoordinate reference frames so that energy can be utilized to target thetissues. SONAR is the acronym for sound navigation and ranging and is amethod of acoustic localization. Sound waves are transmitted through amedium and the time for the sound to reflect back to the transmitter isindicative of the position of the object of interest. Doppler signalsare generated by a moving object. The change in the forward andreflected wave results in a velocity for the object.

The concept of speckle tracking is one in which the reflections ofspecific tissues is defined and tracked over time (IEEE Transactions onUltrasonics, Ferroelectrics, AND Frequency Control, Vol. 57, no. 4,April 2010, herein incorporated by reference). With defined points inspace, a three dimensional coordinate reference can be created throughwhich energy can be applied to specific and well-defined regions. Totrack a speckle, an ultrasound image is obtained from a tissue. Lightand dark spots are defined in the image, these light and dark spotsrepresenting inhomegeneities in the tissues. The inhomegeneities arerelatively constant, being essentially properties of the tissue. Withrelatively constant markers in the tissue, tracking can be accomplishedusing real time imaging of the markers. With more than one plane ofultrasound, the markers can be related in three dimensions relative tothe ultrasound transducer and a therapeutic energy delivered to adefined position within the three dimensional field.

At the time one or more of these imaging modalities is utilized todetermine the position of the target in three dimensions, then a therapycan be both planned and applied to a specific region within the threedimensional volume.

Lithotripsy was introduced in the early part of the 1980's. Lithotripsyutilizes shockwaves to treat stones in the kidney. The Dornierlithotripsy system was the first system produced for this purpose. Thelithotripsy system sends ultrasonic waves through the patient's body tothe kidney to selectively heat and vibrate the kidney stones; that is,selectively over the adjacent tissue. At the present time, lithotripsysystems do not utilize direct targeting and imaging of the kidney stoneregion. A tremendous advance in the technology would be to image thestone region and target the specific region in which the stone residesso as to minimize damage to surrounding structures such as the kidney.In the case of a kidney stone, the kidney is in fact the speckle,allowing for three dimensional targeting and tracking off its image withsubsequent application of ultrasound waves to break up the stone. In theembodiments which follow below, many of the techniques and imagingresults described can be applied to clinical lithotripsy.

Histotripsy is a term given to a technique in which tissue isessentially vaporized using cavitation rather than heating(transcutaneous non-thermal mechanical tissue fractionation). These miniexplosions do not require high temperature and can occur in less than asecond. The generated pressure wave is in the range of megapascals (MPa)and even up to or exceeding 100 MPa. To treat small regions of tissuevery quickly, this technique can be very effective. The border of theviable and non-viable tissue is typically very sharp and the mechanismof action has been shown to be cellular disruption.

In one embodiment, ultrasound is focused on the region of the renalarteries and/or veins from outside the patient; the ultrasound isdelivered from multiple angles to the target, thereby overcoming many ofthe deficiencies in previous methods and devices put forward to ablaterenal sympathetic nerves which surround the renal arteries.

Specifically, one embodiment allows for precise visualization of theablation zone so that the operator can be confident that the correctregion is ablated and that the incorrect region is not ablated. Becausesome embodiments do not require a puncture in the skin, they areconsiderably less invasive, which is more palatable and safer from thepatient standpoint. Moreover, unusual anatomies and atheroscleroticvessels can be treated using external energy triangulated on the renalarteries to affect the sympathetic and afferent nerves to and from thekidney respectively.

With reference to FIG. 1A, the human renal anatomy includes the kidneys100 which are supplied with oxygenated blood by the renal arteries 200and are connected to the heart via the abdominal aorta 300. Deoxygenatedblood flows from the kidneys to the heart via the renal veins (notshown) and thence the inferior vena cava (not shown). The renal anatomyincludes the cortex, the medulla, and the hilum. Blood is delivered tothe cortex where it filters through the glomeruli and is then deliveredto the medulla where it is further filtered through a series ofreabsorption and filtration steps in the loops of henle and individualnephrons; the ultrafiltrate then percolates to the ureteral collectingsystem and is delivered to the ureters and bladder for ultimateexcretion.

The hila is the region where the major vessels (renal artery and renalvein) and nerves 150 (efferent sympathetic, afferent sensory, andparasympathetic nerves) travel to and from the kidneys. The renal nerves150 contain post-ganglionic efferent nerves which supply sympatheticinnervation to the kidneys. Afferent sensory nerves travel from thekidney to the central nervous system and are postganglionic afferentnerves with nerve bodies in the central nervous system. These nervesdeliver sensory information to the central nervous system and arethought to regulate much of the sympathetic outflow from the centralnervous system to all organs including the skin, heart, kidneys, brain,etc.

In one method, energy is delivered from outside a patient, through theskin, and to the renal afferent and/or renal efferent nerves. Microwave,light, vibratory (e.g. acoustic), ionizing radiation might be utilizedin some or many of the embodiments.

Energy transducers 510 (FIG. 1A) deliver energy transcutaneously to theregion of the sympathetic ganglia 520 or the post-ganglionic renalnerves 150 or the nerves leading to the adrenal gland 400. The energy isgenerated from outside the patient, from multiple directions, andthrough the skin to the region of the renal nerves 624 which surroundthe renal artery 620 or the sympathetic ganglion 622 which house thenerves. The energy can be focused or non-focused but in one preferredembodiment, the energy is focused with high intensity focused ultrasound(HIFU) or low intensity focused ultrasound.

Focusing with low intensity focused ultrasound (LIFU) may also occurintentionally as a component of the HIFU (penumbra regions) orunintentionally. The mechanism of nerve inhibition is variable dependingon the “low” or “high” of focused ultrasound. Low energy might includeenergies levels of 25 W/cm²-200 W/cm². Higher intensity includes energylevels from 200 W/cm² to 1 MW/cm². Focusing occurs by delivering energyfrom at least two different angles through the skin to meet at a focalpoint where the highest energy intensity and density occurs. At thisspot, a therapy is delivered and the therapy can be sub-threshold nerveinterruption (partial ablation), ablation (complete interruption) of thenerves, controlled interruption of the nerve conduction apparatus,partial ablation, or targeted drug delivery. The region can be heated toa temperature of less than 60 degrees Celsius for non-ablative therapyor can be heated greater than 60 degrees Celsius for heat baseddestruction (ablation). To ablate the nerves, even temperatures in the40 degree Celsius range can be used and if generated for a time periodgreater than several minutes, will result in ablation. For temperaturesat about 50 degrees Celsius, the time might be under one minute. Heatingaside, a vibratory effect for a much shorter period of time attemperatures below 60 degrees Celsius can result in partial or completeparalysis of destruction of the nerves. If the temperature is increasedbeyond 50-60 degrees Celsius, the time required for heating is decreasedconsiderably to affect the nerve via the sole mechanism of heating. Insome embodiments, an imaging modality is included as well in the system.The imaging modality can be ultrasound based, MRI based, or CT (X-Ray)based. The imaging modality can be utilized to target the region ofablation and determined the distances to the target.

The delivered energy can be ionizing or non-ionizing energy in someembodiments. Forms of non-ionizing energy can include electromagneticenergy such as a magnetic field, light, an electric field,radiofrequency energy, and light based energy. Forms of ionizing energyinclude x-ray, proton beam, gamma rays, electron beams, and alpha rays.In some embodiments, the energy modalities are combined. For example,heat ablation of the nerves is performed and then ionizing radiation isdelivered to the region to prevent re-growth of the nerves.

Alternatively, ionizing radiation is applied first as an ablationmodality and then heat applied afterward in the case of re-growth of thetissue as re-radiation may not be possible (complement or multimodalityenergy utilization). Ionizing radiation may prevent or inhibit there-growth of the nervous tissue around the vessel if there is indeedre-growth of the nervous tissue. Therefore, another method of treatingthe nerves is to first heat the nerves and then apply ionizing radiationto prevent re-growth.

Other techniques such as photodynamic therapy including aphotosensitizer and light source to activate the photosensitizer can beutilized as a manner to combine modalities. Most of thesephotosensitizing agents are also sensitive to ultrasound energy yieldingthe same photoreactive species as if it were activated by light. Aphotoreactive or photosensitive agent can be introduced into the targetarea prior to the apparatus being introduced into the blood vessel; forexample, through an intravenous injection, a subcutaneous injection,etc. However, it will be understood that if desired, the apparatus canoptionally include a lumen for delivering a photoreactive agent into thetarget area. The resulting embodiments are likely to be particularlybeneficial where uptake of the photoreactive agent into the targettissues is relatively rapid, so that the apparatus does not need toremain in the blood vessel for an extended period of time while thephotoreactive agent is distributed into and absorbed by the targettissue.

Light source arrays can include light sources that provide more than onewavelength or waveband of light. Linear light source arrays areparticularly useful to treat elongate portions of tissue. Light sourcearrays can also include reflective elements to enhance the transmissionof light in a preferred direction. For example, devices can beneficiallyinclude expandable members such as inflatable balloons to occlude bloodflow (which can interfere with the transmission of light from the lightsource to the intended target tissue) and to enable the apparatus to becentered in a blood vessel. Another preferred embodiment contemplates atranscutaneous PDT method where the photosensitizing agent deliverysystem comprises a liposome delivery system consisting essentially ofthe photosensitizing agent.

Yet another embodiment of the present invention is drawn to a method fortranscutaneous ultrasonic therapy of a target lesion in a mammaliansubject utilizing a sensitizer agent. In this embodiment, thebiochemical compound is activated by ultrasound through the followingmethod:

1) administering to the subject a therapeutically effective amount of anultrasonic sensitizing agent or a ultrasonic sensitizing agent deliverysystem or a prodrug, where the ultrasonic sensitizing agent orultrasonic sensitizing agent delivery system or prodrug selectivelybinds to the thick or thin neointimas, nerve cells, nerve sheaths, nervenuclei, arterial plaques, vascular smooth muscle cells and/or theabnormal extracellular matrix of the site to be treated. Nervecomponents can also be targeted, for example, the nerve sheath, myelin,S-100 protein. This step is followed by irradiating at least a portionof the subject with ultrasonic energy at a frequency that activates theultrasonic sensitizing agent or if a prodrug, by a prodrug productthereof, where the ultrasonic energy is provided by an ultrasonic energyemitting source. This embodiment further provides, optionally, that theultrasonic therapy drug is cleared from non-target tissues of thesubject prior to irradiation.

A preferred embodiment of this invention contemplates a method fortranscutaneous ultrasonic therapy of a target tissue, where the targettissue is close to a blood vessel.

Other preferred embodiments of this invention contemplate that theultrasonic energy emitting source is external to the patient's intactskin layer or is inserted underneath the patient's intact skin layer,but is external to the blood vessel to be treated. An additionalpreferred embodiment t of this invention provides that the ultrasonicsensitizing agent is conjugated to a ligand and more preferably, wherethe ligand is selected from the group consisting of: a target lesionspecific antibody; a target lesion specific peptide and a target lesionspecific polymer. Other preferred embodiments of the present inventioncontemplate that the ultrasonic sensitizing agent is selected from thegroup consisting of: indocyanine green (ICG); methylene blue; toluidineblue; aminolevulinic acid (ALA); chlorin compounds; phthalocyanines;porphyrins; purpurins; texaphyrins; and any other agent that absorbslight in a range of 500 nm-1100 nm. A preferred embodiment of thisinvention contemplates that the photosensitizing agent is indocyaninegreen (ICG).

Other embodiments of the present invention are drawn to the presentlydisclosed methods of transcutaneous PDT, where the light source ispositioned in proximity to the target tissue of the subject and isselected from the group consisting of: an LED light source; anelectroluminesent light source; an incandescent light source; a coldcathode fluorescent light source; organic polymer light source; andinorganic light source. A preferred embodiment includes the use of anLED light source.

Yet other embodiments of the presently disclosed methods are drawn touse of light of a wavelength that is from about 500 nm to about 1100 nm,preferably greater than about 650 nm and more preferably greater thanabout 700 nm. A preferable embodiment of the present method is drawn tothe use of light that results in a single photon absorption mode by thephotosensitizing agent.

Additional embodiments of the present invention include compositions ofphotosensitizer targeted delivery system comprising: a photosensitizingagent and a ligand that binds a receptor on the target tissue withspecificity. Preferably, the photosensitizing agent of the targeteddelivery system is conjugated to the ligand that binds a receptor on thetarget (nerve or adventitial wall of blood vessel) with specificity.More preferably, the ligand comprises an antibody that binds to areceptor. Most preferably, the receptor is an antigen on thick or thinneointimas, intimas, adventitiaof arteries, arterial plaques, vascularsmooth muscle cells and/or the extracellular matrix of the site to betreated.

A further preferred embodiment of this invention contemplates that thephotosensitizing agent is selected from the group consisting of:indocyanine green (ICG); methylene blue; toluidine blue; aminolevulinicacid (ALA); chlorin compounds; phthalocyanines; porphyrins; purpurins;texaphyrins; and any other agent that absorbs light in a range of 500nm-1100 nm.

Other photosensitizers of the present invention are known in the art,including, Photofrin®, synthetic diporphyrins and dichlorins,phthalocyanines with or without metal substituents, chloroaluminumphthalocyanine with or without varying substituents, chloroaluminumsulfonated phthalocyanine, O-substituted tetraphenyl porphyrins,3,1-meso tetrakis (o-propionamido phenyl) porphyrin, verdins, purpurins,tin and zinc derivatives of octaethylpurpurin, etiopurpurin,hydroporphyrins, bacteriochlorins of the tetra(hydroxyphenyl) porphyrinseries, chlorins, chlorin e6, mono-l-aspartyl derivative of chlorin e6,di-l-aspartyl derivative of chlorin e6, tin(IV) chlorin e6,meta-tetrahydroxphenylchlorin, benzoporphyrin derivatives,benzoporphyrin monoacid derivatives, tetracyanoethylene adducts ofbenzoporphyrin, dimethyl acetylenedicarboxylate adducts ofbenzoporphyrin, Diels-Adler adducts, monoacid ring “a” derivative ofbenzoporphyrin, sulfonated aluminum PC, sulfonated AlPc, disulfonated,tetrasulfonated derivative, sulfonated aluminum naphthalocyanines,naphthalocyanines with or without metal substituents and with or withoutvarying substituents, zinc naphthalocyanine, anthracenediones,anthrapyrazoles, aminoanthraquinone, phenoxazine dyes, phenothiazinederivatives, chalcogenapyrylium dyes, cationic selena andtellurapyrylium derivatives, ring-substituted cationic PC, pheophorbidederivative, pheophorbide alpha and ether or ester derivatives,pyropheophorbides and ether or ester derivatives, naturally occurringporphyrins, hematoporphyrin, hematoporphyrin derivatives,hematoporphyrin esters or ethers, protoporphyrin, ALA-inducedprotoporphyrin IX, endogenous metabolic precursors, 5-aminolevulinicacid benzonaphthoporphyrazines, cationic imminium salts, tetracyclines,lutetium texaphyrin, tin-etio-purpurin, porphycenes,benzophenothiazinium, pentaphyrins, texaphyrins and hexaphyrins, 5-aminolevulinic acid, hypericin, pseudohypericin, hypocrellin, terthiophenes,azaporphyrins, azachlorins, rose bengal, phloxine B, erythrosine,iodinated or brominated derivatives of fluorescein, merocyanines, nileblue derivatives, pheophytin and chlorophyll derivatives,bacteriochlorin and bacteriochlorophyll derivatives, porphocyanines,benzochlorins and oxobenzochlorins, sapphyrins, oxasapphyrins,cercosporins and related fungal metabolites and combinations thereof.

Several photosensitizers known in the art are FDA approved andcommercially available. In a preferred embodiment, the photosensitizeris a benzoporphyrin derivative (“BPD”), such as BPD-MA, alsocommercially known as BPD Verteporfin or “BPD” (available from QLT).U.S. Pat. No. 4,883,790 describes BPD compositions. BPD is asecond-generation compound, which lacks the prolonged cutaneousphototoxicity of Photofrin® (Levy (1994) Semin Oncol 21: 4-10). BPD hasbeen thoroughly characterized (Richter et al., (1987) JNCI79:1327-1331), (Aveline et al. (1994) Photochem Photobiol 59:328-35),and it has been found to be a highly potent photosensitizer for PDT.

In a preferred embodiment, the photosensitizer is tin ethyletiopurpurin, commercially known as purlytin (available from Miravant).

In some embodiments, external neuromodulation is performed in which lowenergy ultrasound is applied to the nerve region to modulate the nerves.For example, it has been shown in the past that low intensity (e.g.non-thermal) ultrasound can affect nerves at powers which range from30-500 mW/Cm² whereas HIFU (thermal modulation), by definition generatesheat at a focus, requires power levels exceeding 1000 W/Cm². The actualpower flux to the region to be ablated is dependent on the environmentincluding surrounding blood flow and other structures. With lowintensity ultrasound, the energy does not have to be so strictly focusedto the target because it's a non-ablative energy; that is, the vibrationor mechanical pressure may be the effector energy and the target mayhave a different threshold for effect depending on the tissue. However,even low energy ultrasound may require focusing if excessive heat to theskin is a worry or if there are other susceptible structures in the pathand only a pinpoint region of therapy is desired. Nonetheless,transducers 500 in FIG. 1 a provide the ability to apply a range ofdifferent energy and power levels as well as modeling capability totarget different regions and predict the response.

In FIG. 1 a, and in one embodiment, a renal artery 640 is detected withthe assistance of imaging devices 600 such as Doppler ultrasound,infrared imaging, thermal imaging, B-mode ultrasound, MRI, or a CT scan.With an image of the region to be treated, measurements in multipledirections on a series of slices can be performed so as to create athree-dimensional representation of the area of interest. By detectingthe position of the renal arteries from more than one angle via Dopplertriangulation (for example) or another triangulation technique, a threedimensional positional map can be created and the renal artery can bemapped into a coordinate reference frame. In this respect, given thatthe renal nerves surround the renal blood vessels in the hilum, locatingthe direction and lengths of the blood vessels in three dimensionalcoordinate reference is the predominant component of the procedure totarget these sympathetic nerves. Within the three dimensional referenceframe, a pattern of energy can be applied to the vicinity of the renalartery from a device well outside the vicinity (and outside of thepatient altogether) based on knowledge of the coordinate referenceframe.

For example, once the renal artery is placed in the coordinate referenceframe with the origin of the energy delivery device, an algorithm isutilized to localize the delivery of focused ultrasound to heat or applymechanical energy to the adventitia and surrounding regions of theartery which contain sympathetic nerves to the kidney and afferentnerves from the kidney, thereby decreasing the sympathetic stimulus tothe kidney and decreasing its afferent signaling back to the autonomicnervous system; affecting these targets will modulate the propensitytoward hypertension which would otherwise occur. The ultrasonic energydelivery can be modeled mathematically by predicting the acoustic wavedissipation using the distances and measurements taken with the imagingmodalities of the tissues and path lengths.

In one embodiment of an algorithm, the Doppler signal from the artery isidentified from at least two different directions and the direction ofthe artery is reconstructed in three dimensional space. With two pointsin space, a line is created and with knowledge of the thickness of thevessel, a tube, or cylinder, can be created to represent the bloodvessel as a virtual model. The tube is represented in three dimensionalspace over time and its coordinates are known relative to thetherapeutic transducers outside of the skin of the patient. Therapeuticenergy can be applied from more than one direction as well and can focuson the cylinder (blood anterior vessel wall, central axis, or posteriorwall).

Focused energy (e.g. ultrasound) can be applied to the center of thevessel (within the flow), on the posterior wall of the vessel, inbetween (e.g. when there is a back to back artery and vein next to oneanother) the artery vessel and a venous vessel, etc.

Imaging 600 of the sympathetic nerves or the sympathetic region (thetarget) is also utilized so as to assess the direction and orientationof the transducers relative to the target 620; the target is an internalfiducial, which in one embodiment is the kidney 610 and associated renalartery 620 because they can be localized via thier blood flow, a modelthen produced around it, and then they both can be used as a target forthe energy. Continuous feedback of the position of the transducers 500,510 relative to the target 620 is provided by the imaging system inwhich the coordinate space of the imaging system. The imaging may be across-sectional imaging technology such as CT or MRI or it may be anultrasound imaging technology which yields faster real time imaging. Insome embodiments, the imaging may be a combination of technologies suchas the fusion of MRI/CT and ultrasound. The imaging system can detectthe position of the target in real time at frequencies ranging from 1 Hzto thousands and tens of thousands of images per second.

In the example of fusion, cross-sectional imaging (e.g. MRI/CT) isutilized to place the body of the patient in a three dimensionalcoordinate frame and then ultrasound is linked to the three dimensionalreference frame and utilized to track the patient's body in real timeunder the ultrasound linked to the cross-sectional imaging. The lack ofresolution provided by the ultrasound is made up for by thecross-sectional imaging since only a few consistent anatomic landmarksare required for an ultrasound image to be linked to the MRI image. Asthe body moves under the ultrasound, the progressively new ultrasoundimages are linked to the MRI images and therefore MRI “movement” can beseen at a frequency not otherwise available to an MRI series.

In one embodiment, ultrasound is the energy used to inhibit nerveconduction in the sympathetic nerves. In one embodiment, focusedultrasound (HIFU) from outside the body through the skin is the energyused to inhibit sympathetic stimulation of the kidney by deliveringwaves from a position external to the body of a patient and focusing thewaves on the sympathetic nerves on the inside of the patient and whichsurround the renal artery of the patient.

As is depicted in FIG. 3 a-b, transducers 900 can emit ultrasound energyfrom a position outside the patient to the region of the renalsympathetic nerves at the renal pedicle 200. As shown in FIG. 1 a, animage of the renal artery 620 using an ultrasound, MRI, or CT scan canbe utilized to determine the position of the kidney 610 and the renalartery 620 target. Doppler ultrasound can be used to determine thelocation and direction of a Doppler signal from an artery and place thevessel into a three dimensional reference frame 950, thereby enablingthe arteries 200 and hence the sympathetic nerves 220 (FIG. 3 a) aroundthe artery to be much more visible so as to process the images and thenutilize focused external energy to pinpoint the location and therapy ofthe sympathetic nerves. In this embodiment, ultrasound is likely themost appropriate imaging modality.

FIG. 1 a also depicts the delivery of focused energy to the sympatheticnerve trunks and ganglia 622 which run along the vertebral column andaorta 300; the renal artery efferent nerves travel in these trunks andsynapse to ganglia within the trunks. In another embodiment, ablation ofthe dorsal and ventral roots at the level of the ganglia or dorsal rootnerves at T9-T11 (through which the afferent renal nerves travel) wouldproduce the same or similar effect to ablation at the level of the renalarteries.

In another embodiment, FIG. 1 b illustrates the application of ionizingenergy to the region of the sympathetic nerves on the renal arteries 620and/or renal veins. In general, energy levels of greater than 20 Gy(Gray) are required for linear accelerators or low energy x-ray machinesto ablate nervous tissue using ionizing energy; however, lower energy isrequired to stun, inhibit nervous tissue, or prevent re-growth ofnervous tissue; in some embodiment, ionizing energy levels as low as 2-5Gy or 5-10 Gy or 10-15 Gy are delivered in a single or fractionateddoses.

Combinations of ionizing energy and other forms of energy can beutilized in this embodiment as well so as to prevent re-growth of thenervous tissue. For example, a combination of heat and/or vibrationand/or cavitation and/or ionizing radiation might be utilized to preventre-growth of nervous tissue after the partial or full ablation of thenervous tissue surrounding the renal artery.

FIG. 2 illustrates the renal anatomy and surrounding anatomy withgreater detail in that organs such as the stomach 700 are shown in itsanatomic position overlying the abdominal aorta 705 and renal arteries715. In this embodiment, energy is delivered through the stomach toreach an area behind the stomach. In this embodiment, the stomach isutilized as a conduit to access the celiac ganglion 710, a region whichwould otherwise be difficult to reach. The aorta 705 is shown underneaththe stomach and the celiac ganglion 710 is depicted surrounding thesuperior mesenteric artery and aorta. A transorally placed tube 720 isplaced through the esophagus and into the stomach. The tube overlies theceliac ganglion when placed in the stomach and can therefore be used todeliver sympatholytic devices or pharmaceuticals which inhibit orstimulate the autonomic celiac ganglia behind the stomach; thesetherapies would be delivered via transabdominal ultrasound orfluoroscopic guidance (for imaging) through the stomach. Similartherapies can be delivered to the inferior mesenteric ganglion, renalnerves, or sympathetic nerves traveling along the aorta through thestomach or other portion of the gastrointestinal tract. The energydelivery transducers 730,731 are depicted external to the patient andcan be utilized to augment the therapy being delivered through thestomach to the celiac ganglion. Alternatively, the energy deliverytransducers can be utilized for imaging the region of therapy.

In one embodiment, energy is applied to the region of the celiacganglion from a region outside the patient. In this embodiment, fluid isplaced into the gastrointestinal system, such as for example, in thestomach or small intestine. Ultrasound can then be transmitted throughthe gastrointestinal organs to the ganglia of interest behind thestomach.

Temporary neurostimulators can also be placed through the tube, such as,for example, in an ICU setting where temporary blockage of the autonomicganglia may be required. Temporary neurostimulators can be used to overpace the celiac ganglion nerve fibers and inhibit their function as anerve synapse Inhibition of the celiac ganglion may achieve a similarfunction as ablation or modulation of the sympathetic nerves around therenal arteries. That is, the decrease in the sympathetic activity to thekidneys (now obtained with a more proximal inhibition) leads to thelowering of blood pressure in the patient by decreasing the degree ofsympathetic outflow from the sympathetic nerve terminals. In the celiacganglia, the blood pressure lowering effect is more profound given thatthe celiac ganglia are pre-ganglionic and have more nerve fibers to agreater number of regions than each renal nerve. The effect is alsolikely more permanent than the effect on the post-ganglionic nervefibers.

FIG. 3 a illustrates the renal anatomy more specifically in that therenal nerves 220 extending longitudinally along the renal artery 200,are located generally within, or just outside the adventitia, of theouter portion of the artery. Arteries are typically composed of threelayers: the first is the intimal, the second is the media, and the thirdis the adventitia. The outer layer, the adventitia, is a fibrous tissuewhich contains blood vessels and nerves. The renal nerves are generallypostganglionic sympathetic nerves although there are some ganglia whichexist distal to the takeoff from the aorta such that some of the nervefibers along the renal artery are in fact pre-ganglionic. By the timethe fibers reach the kidney, the majority of the fibers arepost-ganglionic. The afferent nerves on the other hand leave the kidneyand are post-ganglionic up to the level of the brain. These fibers do nore-grow as quickly as the efferent fibers, if at all.

Energy generators 900 deliver energy to the renal nerves accompanyingthe renal artery, depositing energy from multiple directions to targetinhibition of the renal nerve complex. The energy generators can deliverultrasound energy, ionizing radiation, light (photon) therapy, ormicrowave energy to the region. The energy can be non-focused in thecase where a pharmaceutical agent is targeted to the region to beablated or modulated. Preferably, however, the energy is focused, beingapplied from multiple angles from outside the body of the patient toreach the region of interest (e.g. sympathetic nerves surrounding bloodvessels). The energy transducers 900 are placed in an X-Y-Z coordinatereference frame 950, as are the organs such as the kidneys. The x-y-zcoordinate frame is a real space coordinate frame. For example, realspace means that the coordinate reference is identifiable in thephysical world; like a GPS (global positioning system), with thephysical coordinates, a physical object can be located. Once in thex-y-z coordinate reference frame, cross-sectional imaging using MRI, CTscan, and/or ultrasound is utilized to couple the internal anatomy tothe energy transducers. These same transducers may be utilized for thedetermination of the reference point as well as the therapy. Thetransducers 900 in this embodiment are focused on the region of therenal nerves at the level of the renal blood vessels, the arteries andveins 200. The focus of the beams can be inside the artery, inside thevein, on the adventitia of the artery or adventitia of the vein.

When applying ultrasonic energy across the skin to the renal arteryregion, energy densities of potentially over 1 MW/cm² might be requiredat region of interest in the adventitia of the blood vessel. Typically,however, power densities of 100 W/cm² to 3 kW/cm² would be expected tocreate the heating required to inhibit these nerves (see Foley et. al.Image-Guided HIFU Neurolysis of Peripheral Nerves To Treat SpasticityAnd Pain; Ultrasound in Med & Biol. Vol 30 (9) p 1199-1207 hereinincorporated by reference). The energy may be pulsed across the skin inan unfocused manner; however, for application of heat, the transducersmust be focused otherwise the skin and underlying tissues will receivetoo much heat. Under imaging with MRI, temperature can be measured withthe MRI image. When low energy ultrasound is applied to the region,energy (power) densities in the range of 50 mW/cm² to 500 mW/cm² may beapplied. Low energy ultrasound may be enough to stun or partiallyinhibit the renal nerves particularly when pulsed and depending on thedesired clinical result. High intensity ultrasound applied to the regionwith only a few degrees of temperature rise may have the same effect andthis energy range may be in the 0.1 kW/cm2 to the 500 kW/cm2 range. Atrain of pulses also might be utilized to augment the effect on nervoustissue. For example, a train of 100 short pulses, each less than asecond and applying energy densities of 1 W/cm² to 500 W/cm². In some ofthe embodiments, cooling may be applied to the skin if the temperaturerise is deemed too large to be acceptable. Alternatively, the ultrasoundtransducers can be pulsed or can be alternated with another set oftransducers to effectively spread the heat across the surface of theskin. In some embodiments, the energy is delivered in a pulsed fashionto further decrease the risk to the intervening tissues between thetarget and the transducer. The pulses can be as close as millisecond, asdescribed, or as long as hours, days or years.

In one method of altering the physiologic process of renal sympatheticexcitation, the region around the renal arteries is imaged using CTscan, MRI, thermography, infrared imaging, optical coherence tomography(OCT), photoacoustic imaging, pet imaging, SPECT imaging, or ultrasound,and the images are placed into a three dimensional coordinate referenceframe 950. The coordinate reference frame 950 refers to the knowledge ofthe relationship between anatomic structures, both two dimensional andthree dimensional, the structures placed into a physical coordinatereference. Imaging devices determine the coordinate frame. Once thecoordinate frame is established, the imaging and therapy transducers 900can be coupled such that the information from the imaging system isutilized by the therapeutic transducers to position the energy. Bloodvessels may provide a useful reference frame for deposition of energy asthey have a unique imaging signature. An ultrasound pulse echo canprovide a Doppler shift signature to identify the blood vessel from thesurrounding tissue. In an MRI, CT scan, and even an ultrasound exam,intravenous contrast agents can be utilized to identify flow patternsuseful to determine a coordinate reference for energy deposition. Energytransducers 900 which can deliver ultrasound, light, radiation, ionizingradiation, or microwave energy are placed in the same three-dimensionalreference frame as the renal arteries, at which time a processor (e.g.using an algorithm) can determine how to direct the transducers todeliver energy to the region 220 of the nerves 910. The algorithmconsists of a targeting feature (planning feature) which allows forprediction of the position and energy deposition of the energy leavingthe transducers 900.

Once the three dimensional coordinate reference frames 950 are linked orcoupled, the planning and prediction algorithm can be used to preciselyposition the energy beams at a target in the body.

The original imaging modality can be utilized to locate the renalsympathetic region can be used to track the motion of the region duringtreatment. For example, the imaging technology used at time zero istaken as the baseline scan and subsequent scans at time t1 are comparedto the baseline scan, t0. The frequency of updates can range from asingle scan every few seconds to many scans per second. With ultrasoundas the imaging technology, the location might be updated at a frame rategreater than 50 Hz and up to several hundred Hz or thousand Hz. With MRIas the imaging modality, the imaging refresh rate might be closer to 30Hz. In other embodiments, internally placed fiducials transmitpositional information at a high frequency and this information isutilized to fuse the target with an initial external imaging apparatus.Internal fiducials might include one or more imageable elementsincluding doppler signals, regions of blood vessels, ribs, kidneys, andblood vessels and organs other than the target (e.g. vena cava, adrenalgland, ureter). These fiducials can be used to track the region beingtreated and/or to triangulate to the region to be treated.

In some embodiments (FIG. 3C), a temporary fiducial 960 is placed in theregion, such as in the artery 965, renal vein 975, aorta 945, and/orvena cava 985; such a fiducial is easily imageable from outside thepatient.

FIG. 3D depicts an imageable transducer 960 in a blood vessel 967 withina coordinate reference 975 on a monitor system 950. Alternatively, thetemporary fiducial 960 is a transducer which further improves theability to image and track the region to deliver therapy. The temporaryfiducial might be a mechanical, optical, electromechanical, aradiofrequency radiotransmitter, global positioning tracking (GPS)device, or ultrasound responsive technology. Similar devices might befound in U.S. Pat. Nos. 6,656,131 and 7,470,241 which are incorporatedby reference herein.

Internal reflections (e.g. speckles) can be tracked as well. Thesespeckles are inherent characteristics of tissue as imaged withultrasound. They can be tracked and incorporated into treatment planningalgorithm and then linked to the therapeutic transducers.

In some embodiments, a test dose of energy can be applied to the renalsympathetic region and then a test performed to determine if an effectwas created. For example, a small amount of heat or vibratory energy canbe delivered to the region of the sympathetic nerves and then a test ofsympathetic activity such as microneurography (detection of sympatheticnerve activity around muscles and nerves which correlate with thebeating heart) can be performed. Past research and current clinical datahave shown that the sympathetic nerves to the peripheral muscles areaffected by interruption of the renal afferent nerves. The degree oftemperature rise with the small degree of heat can be determined throughthe use of MRI thermometry or an ultrasound technique and thetemperature rise can be determined or limited to an amount which isreversible.

In another embodiment, a stimulus is applied to a region such as theskin and an output downstream from the skin is detected. For example, avibratory energy might be applied to the skin and a sympathetic outflowsuch as the heart rate might be detected. In another embodiment, heat orcold might be applied to the skin and heart rate, blood pressure;vasoconstriction might be detected as an output.

Alternatively, ultrasonic imaging can be utilized to determine theapproximate temperature rise of the tissue region. The speed ofultrasonic waves is dependent on temperature and therefore the relativespeed of the ultrasound transmission from a region being heated willdepend on the temperature, therefore providing measureable variables tomonitor. In some embodiments, microbubbles are utilized to determine therise in temperature. Microbubbles expand and then degrade when exposedto increasing temperature so that they can then predict the temperatureof the region being heated. A technique called ultrasound elastographycan also be utilized. In this embodiment, the elastic properties oftissue are dependent on temperature and therefore the elastography maybe utilized to track features of temperature change. The microbubblescan also be utilized to augment the therapeutic effect of the regionbeing targeted. For example, the microbubbles can be utilized to releasea pharmaceutical when the ultrasound reaches them. Alternatively, themicrobubble structure can be utilized to enhance imaging of thetreatment region to improve targeting or tracking of the treatmentregion.

In some embodiments, only the temperature determination is utilized.That is, the temperature sensing embodiments and algorithms are utilizedwith any procedure in which heating is being performed. For example, ina case where heating of the renal nerve region is performed usingradiofrequency ablation through the renal artery, imaging of the regionfrom a position external to the patient can be performed while the renalartery region is being heated via radiofrequency methods. Imaging can beaccomplished utilizing MRI, ultrasound, infrared, or OCT methods.

In another embodiment, a test may be performed on the baroreceptorcomplex at the region of the carotid artery bifurcation. After the testdose of energy is applied to the renal artery complex, pressure can beapplied to the carotid artery complex; typically, with an intactbaroreceptor complex, the systemic blood pressure would decrease afterapplication of pressure to the carotid artery. However, with renalafferent nerves which have been inhibited, the baroreceptors will not besensitive to changes in blood pressure and therefore the efficacy of theapplication of the energy to the renal nerves can be determined. Othertests include attaining indices of autonomic function such asmicroneurography, autonomic function variability, etc.

In another embodiment, stimulation of the baroreceptor complex isaccomplished non-invasively via ultrasound pulses applied externally tothe region of the carotid body. The ultrasound pulses are sufficient tostimulate the sinus to affect a blood pressure change, a change whichwill be affected when an afferent nerve such as the renal afferents havebeen altered.

More specifically, this methodology is depicted in FIG. 3E. Anultrasound pulse 980 is utilized to stimulate the carotid sinus whichwill lower blood pressure transiently 982 by activating the baroreceptorcomplex; activation of the carotid sinus 980 simulates the effect of anincrease in blood pressure which leads to a compensatory outflow ofparasympathetic activity and decreased sympathetic outflow, subsequentlylowering blood pressure. In the instance when the afferent system (e.g.from the kidney) has been inhibited, the pressure will not be modifiableas quickly if at all. In this case, stimulating the baroreceptor complexdoes not result in a lowering of blood pressure 986, then the treatmentwas successful. This diagnostic technique can therefore be utilized todetermine the effect of a therapy on a system such as the renal nervecomplex. If therapy is successful, then the modifying effect of theultrasound pulse on the carotid sinus and blood pressure is lessdramatic and the therapeutic (treatment of afferent nerves) successful;therefore, therapy can be discontinued 988 temporarily or permanently.If the blood pressure continues to decrease 982 with the baroreceptorstimulation, then the therapeutic effect has not been reached with thetherapeutic treatment and it needs to be continued 984 and/or the doseincreased. Other methods to stimulate the baroreceptor complex are toapply pressure in the vicinity with hands, compression balloons, and thelike.

Other regions of the autonomic nervous system can also be affecteddirectly by the technology described herein by applying energy from oneregion and transmitted through tissue to another region. For example,FIG. 4 a illustrates a system in which energy external to the internalcarotid artery 1020 is applied to a portion of the autonomic nervoussystem, the carotid body complex 1000, through the internal jugular vein1005, and to the carotid body 1000 and/or vagus nerve 1020 region.Ablative energy, vibratory, or electrical stimulation energy can beutilized to affect the transmission of signals to and from these nerves.The transmission in this complex can be augmented, interrupted,inhibited with over-stimulation, or a combination of these effects viaenergy (e.g. ultrasound, electrical stimulation, etc.).

In addition, or in place of, in other embodiments, energy may be appliedto peripheral nerves typically known as motor nerves but which containautonomic fibers. Such nerves include the saphenous nerve, femoralnerves, lumbar nerves, median nerves, ulnar nerves, and radial nerves.In some embodiments, energy is applied to the nerves and specificautonomic fibers are affected rather than the other neural fibers (e.g.motor or somatic sensory fibers or efferent or afferent autonomicnerves). In some embodiments, other types of autonomic fibers areaffected with energy applied internally or externally. For example,nerves surrounding the superior mesenteric artery, the inferiormesenteric artery, the femoral artery, the pelvic arteries, etc. can beaffected by the energy in a specific manner so as to create changes inthe autonomic responses of the blood vessels themselves or organsrelated to the blood vessels, the nerves running through and along thevessels to the organs.

In another embodiment, in FIG. 4 a, a catheter 1010 is advanced into theinternal jugular vein 1005 and when in position, stimulation or ablativeenergy 1020 is directed toward the autonomic nerves, e.g. the vagusnerve and the carotid sinus/body 1000, from the catheter positioned inthe venous system 1005.

In a similar type of embodiment 1100, a catheter based therapeuticenergy source 1110 can be inserted into the region of the renal arteriesor renal veins (FIG. 4B) to stimulate or inhibit the renal nerves fromthe inside of the vessel, either the renal artery 1105 or renal vein1106. Energy is transferred through the vessel (e.g. renal vein) toreach the nerves around another vessel (e.g. renal artery). For example,a catheter delivering unfocused ultrasound energy with powers in therange of 50 mW/cm² to 50 kW/cm² can be placed into the renal artery andthe energy transmitted radially around the artery or vein to thesurrounding nerves. As discussed below, the 500 mW-2500 W/cm² isappropriate to create the specific nerve dysfunction to affect thenorepinephrine levels in the kidney, a surrogate of nerve function whichhas been shown to lead to decreases in blood pressure over time. Pulsedultrasound, for example, 100 pulse trains with each lasting less than 1second each, can be applied to the region.

In another embodiment, light is applied through the vessel from withinthe blood vessel. Infrared, red, blue, and near infrared can all beutilized to affect the function of nerves surrounding blood vessels. Forexample, a light source is introduced into the renal artery or renalvein 1105, 1106 and the light transmitted to the region surrounding theblood vessels. In a preferred embodiment, a photosensitizing agent isutilized to hasten the inhibition or destruction of the nerve bundleswith this technique. Photosensitizing agents can be applied systemicallyto infiltrate the region around the blood vessels. Light is then appliedfrom inside the vessel to the region of the nerves outside the vessel.For example, the light source is placed inside the renal vein and thenlight is transmitted through the vein wall to the adventitial regionaround the wall activating the photosensitizer and injuring orinhibiting the nerves in the adventitia through an apoptosis pathway.The light source may provide light that is visible, or light that isnon-visible.

The therapies in FIGS. 4 a-b can be delivered on an acute basis such asfor example in an ICU or critical care setting. In such a case, thetherapy would be acute and intermittent, with the source outside thepatient and the catheter within the patient as shown in FIGS. 4 a-b. Thetherapy can be utilized during times of stress for the patient such thatthe sympathetic system is slowed down. After the intensive careadmission is nearing a close, the catheter and unit can be removed fromthe patient. In one embodiment, a method is described in which acatheter is placed within a patient to deliver energy to a region of thebody sufficient to partially or fully inhibit an autonomic nerve complexduring a state of profound sympathetic activation such as shock, sepsis,myocardial infarction, pancreatitis, post-surgical. After the acutephase of implantation during which the sympathetic system is modulated,the device is removed entirely.

FIGS. 5 a-b illustrates the eye in close up detail with sympatheticnerves surrounding the posterior of the eye. In the eye, glaucoma is aproblem of world-wide importance. The most commonly prescribedmedication to treat glaucoma is timoptic, which is a non-selective β1and β2 (adrenergic) antagonist. Compliance with this pharmaceutical is amajor problem and limits its effectiveness in preventing thecomplications of glaucoma, the major complication being progression ofvisual dysfunction.

Ultrasound, or other energy transducers 7000, can be applied to focusenergy from an external region (e.g. a distance from the eye in anexternal location) anterior to the eye or to a region posteriorly behindthe eye 2500 on the sympathetic 2010 or parasympathetic ganglia, all ofwhich will affect lowering of intra-ocular pressure. The energytransducers 7000 apply ablative or near ablative energy to theadventitia of the blood vessels. In some embodiments, the energy is notablative but vibratory at frequencies (e.g. 1-5 Mhz) and penetrationdepths (e.g. 0.5 mm to 0.5 cm) sufficient to inhibit the function of thenerves which are responsible for intra-ocular pressure. Lower energy(e.g. sub-ablative) can be applied to the eye to assist in drug deliveryor to stimulate tissue healing type of tissue responses.

FIG. 5 b depicts the anatomy of the nerves which travel behind the eye2500. In this illustration, a catheter 2000 is tunneled through thevasculature to the region of the sympathetic nerves surrounding thearteries of the eye 2010 and utilized to ablate, stun, or otherwisemodulate the efferent and/or afferent nerves through the wall of thevasculature.

FIG. 6 illustrates an overall schematic of the renal artery, renal vein,the collecting system, and the more distal vessels and collecting systemwithin the renal parenchyma. The individual nerves of the autonomicnervous system typically follow the body vasculature and they are shownin close proximity 3000 to the renal artery as the artery enters thekidney 3100 proper. The hilum of the kidney contains pressure sensorsand chemical sensors which influence the inputs to the efferentsympathetic system via afferent nerves traveling from the kidney to thecentral nervous system and then to the efferent nervous system. Any oneor multiple of these structures can influence the function of thekidney. Ablative or non-ablative energy can be applied to the renalvein, the renal artery, the aorta, and/or the vena cava, the renalhilum, the renal parenchyma, the renal medulla, the renal cortex, etc.

In another embodiment, selective lesions, constrictions or implants 3200are placed in the calyces of the kidney to control or impede blood flowto specific regions of the kidney. Such lesions or implants can beplaced on the arterial 3010 or venous sides 3220 of the kidney. In someembodiments, the lesions/implants are created so as to selectively blockcertain portions of the sympathetic nerves within the kidney. Thelesions also may be positioned so as to ablate regions of the kidneywhich produce hormones, such as renin, which can be detrimental to apatient in excess. The implants or constrictions can be placed in theaorta 3210 or the renal vein 3230. The implants can be active implants,generating stimulating energy chronically or multiple ablative orinhibitory doses discretely over time.

In the renal vein 3230, the implants 3220, 3200 might cause an increasein the pressure within the kidney (by allowing blood flow to back upinto the kidney and increase the pressure) which will prevent thedownward spiral of systolic heart failure described above because thekidney will act as if it is experiencing a high pressure head. That is,once the pressure in the kidney is restored or artificially elevated byincreased venous pressure, the relative renal hypotension signaling toretain electrolytes and water will not be present any longer and thekidney will “feel” full and the renal sympathetic stimulation will beturned off. In one embodiment, a stent which creates a stenosis isimplanted using a catheter delivery system. In another embodiment, astricture 3220 is created using heat delivered either externally orinternally. Externally delivered heat is delivered via direct heatingvia a percutaneous procedure (through the skin to the region of thekidney) or transmitted through the skin (e.g. with HIFU focused throughthe skin). In one embodiment, an implant is placed between girota'sfascia and the cortex of the kidney. The implant can stimulate orinhibit nerves surrounding the renal blood vessels, or even releasepharmaceuticals in a drug delivery system.

FIG. 7 a depicts at least partial ablation of the renal sympatheticnerves 4400 to the kidney using an imaging system such as an MRI machineor CT scanner 4000. The MRI/CT scan can be linked to a focusedultrasound (HIFU) machine to perform the ablations of the sympatheticnerves 4400 around the region of the renal artery 4500. The MRI/CT scanperforms the imaging 4010 and transmits data (e.g. three dimensionalrepresentations of the regions of interest) to the ultrasound controllerwhich then directs the ultrasound to target the region of interest withlow intensity ultrasound (50-1000 mW/cm2), heat (>1000 mW/cm2),cavitation, or a combination of these modalities and/or includingintroduction of enhancing bioactive agent delivery locally orsystemically (sonodynamic therapy). Optionally, a doppler ultrasound orother 3D/4D ultrasound is performed and the data pushed to the MRIsystem to assist with localization of the pathology; alternatively, theultrasound data are utilized to directly control the direction of theenergy being used to target the physiologic processes and CT/MRI is notobtained. Using this imaging and ablation system from a positionexternal to a patient, many regions of the kidney can be treated such asthe internal calyces 4350, the cortex 4300, the medulla 4320, the hilum4330, and the region 4340 close to the aorta.

Further parameters which can be measured include temperature via thermalspectroscopy using MRI or ultrasound thermometry/elastography; thermalimaging is a well-known feature of MRI scanners; the data for thermalspectroscopy exists within the MRI scan and can be extrapolated from therecorded data in real time by comparing regions of interest before andafter or during treatment. Temperature data overlaid on the MRI scanenables the operator of the machine to visualize the increase intemperature and therefore the location of the heating to insure that thecorrect region has indeed been ablated and that excessive energy is notapplied to the region. Having temperature data also enables control ofthe ablation field as far as applying the correct temperature forablation to the nerves. For example, the temperature over time can bedetermined and fed back to the operator or in an automated system, tothe energy delivery device itself. Furthermore, other spectroscopicparameters can be determined using the MRI scan such as oxygenation,blood flow, or other physiologic and functional parameters. In oneembodiment, an alternating magnetic field is used to stimulate and thenover-stimulate or inhibit an autonomic nerve (e.g. to or from thekidney).

Elastography is a technique in which the shear waves of the ultrasoundbeam and reflectance are detected. The tissue characteristics change asthe tissue is heated and the tissue properties change. An approximatetemperature can be assigned to the tissue based on elastography and theprogress of the heating can be monitored.

MRI scanners 4000 generally consist of a magnet and an RF coil. Themagnet might be an electromagnet or a permanent magnet. The coil istypically a copper coil which generates a radiofrequency field.Recently, permanent magnets have been utilized to create MRI scannerswhich are able to be used in almost any setting, for example a privateoffice setting. Office based MRI scanners enable imaging to be performedquickly in the convenience of a physician's office as well as requiringless magnetic force (less than 0.5 Tesla) and as a consequence, lessshielding. The lower tesla magnets also provides for special advantagesas far as diversity of imaging and resolution of certain features.Importantly, the permanent magnet MRI scanners are open scanners and donot encapsulate the patient during the scan.

In one embodiment, a permanent magnet MRI is utilized to obtain an MRIimage of the region of interest 4010. High intensity focused 4100ultrasound is used to target the region of interest 4600 identifiedusing the MRI. In one embodiment, the MRI is utilized to detect bloodflow within one or more blood vessels such as the renal arteries, renalveins, superior mesenteric artery, veins, carotid arteries and veins,aortic arch coronary arteries, veins, to name a subset.

Image 4010 is or can be monitored by a health care professional toensure that the region of interest is being treated and the treatmentcan be stopped if the assumed region is not being treated.Alternatively, an imaging algorithm can be initiated in which the regionof interest is automatically (e.g. through image processing) identifiedand then subsequent images are compared to the initial demarcated regionof interest.

Perhaps, most importantly, with MRI, the region around the renalarteries can be easily imaged as can any other region such as the eye,brain, prostate, breast, liver, colon, spleen, aorta, hip, knee, spine,venous tree, and pancreas. The imaging from the MRI can be utilized toprecisely focus the ultrasound beam to the region of interest around therenal arteries or elsewhere in the body. With MRI, the actual nerves tobe modified or modulated can be directly visualized and targeted withthe energy delivered through the body from the ultrasound transducers.One disadvantage of MRI can be the frame acquisition (difficulty intracking the target) rate as well as the cost of introducing an MRImachine into the treatment paradigm. In these regards, ultrasoundimaging offers a much more practical solution.

FIG. 7 d depicts a method of treating a region with high intensityfocused ultrasound (HIFU). Imaging with an MRI 4520 or ultrasound 4510(or preferably both) is performed. MRI can be used to directly orindirectly (e.g. using functional MRI or spectroscopy) to visualize thesympathetic nerves. T1 weighted or T2 weighted images can be obtainedusing the MRI scanner. In addition to anatomic imaging, the MRI scannercan also obtain temperature data regarding the effectiveness of theablation zone as well as the degree to which the zone is being heatedand which parts of the zones are being heated. Other spectroscopicparameters can be added as well such as blood flow and even nerveactivity. Ultrasound 4510 can be used to add blood flow to the imagesusing Doppler imaging. The spectroscopic data can be augmented byimaging moieties such as particles, imaging agents, or particles coupledto imaging agents which are injected into the patient intravenously, orlocally, and proximal to the region of the renal arteries; these imagingmoieties may be visualized on MRI, ultrasound, or CT scan. Ultrasoundcan also be utilized to determine information regarding heating. Thereflectance of the ultrasonic waves changes as the temperature of thetissue changes. By comparing the initial images with the subsequentimages after heating, the temperature change which occurred after theinstitution of heating can be determined.

In one embodiment, the kidneys are detected by a cross-sectional imagingmodality such as MRI, ultrasound, or CT scan. The renal arteries andveins are detected within the MRI image utilizing contrast or notutilizing contrast. Next, the imaging data is placed into a threedimensional coordinate system which is linked to one or more ultrasound(e.g. HIFU) transducers 4540 which focus ultrasound onto the region ofthe renal arteries in the coordinate frame 4530. The linking, orcoupling, of the imaging to the therapeutic transducers is accomplishedby determining the 3 dimensional position of the target by creating ananatomic model. The transducers are placed in a relative threedimensional coordinate frame as well. For example, the transducers canbe placed in the imaging field 4520 during the MRI or CT scan such thatthe cross-sectional pictures include the transducers. Optionally, thetransducers contain motion sensors, such as electromagnetic, optical,inertial, MEMS, and accelerometers, one or more of which allow for thetransducer position to be monitored if for example the body movesrelative to the transducer or the operator moves relative to the body.With the motion sensors, the position of the transducers can bedetermined with movement which might occur during the therapy. Theupdated information can then be fed back to the ultrasound therapydevice so as to readjust the position of the therapy.

In one embodiment, a system is described in which the blood flow in therenal artery is detected by detecting the walls of the artery or renalvein or the blood flow in the renal artery or the renal vein. Thecoordinate reference of the blood vessels is then transmitted to thetherapeutic transducer, for example, ultrasound. The therapeutictransducer is directed to the renal blood vessels using the informationobtained by imaging. A model of the vessels indicates the blood flow ofthe vessels and the walls of the vessels where the nerves reside. Energyis then applied to the model of the vessels to treat the nerves aroundthe vessels.

Alternatively, in another embodiment, ultrasound is utilized and theultrasound image 4510 can be directly correlated to the origin of theimaging transducer. The therapeutic transducer 4540 in some embodimentsis the same as the imaging transducer and therefore the therapeutictransducer is by definition coupled in a coordinate reference 4540 oncethe imaging transducer coordinates are known. If the therapeutictransducer and the imaging transducer are different devices, then theycan be coupled by knowledge of the relative position of the two devices.The region of interest (ROI) is highlighted in a software algorithm; forexample, the renal arteries, the calyces, the medullary region, thecortex, the renal hila, the celiac ganglia, the aorta, or any of theveins of the venous system as well. In another embodiment, the adrenalgland, the vessels traveling to the adrenal gland, or the autonomicnerves traveling to the adrenal gland are targeted with focusedultrasound and then either the medulla or the cortex of the adrenalgland or the nerves and arteries leading to the gland are partially orfully ablated with ultrasonic energy.

The targeting region or focus of the ultrasound is the point of maximalintensity. In some embodiments, targeting focus is placed in the centerof the artery such that the walls on either side receive equivalentamounts of energy or power and can be heated more evenly than if onewall of the blood vessel is targeted. In some embodiments in which ablood vessel is targeted, the blood vessel being an artery and theartery having a closely surrounding vein (e.g. the renal artery/veinpedicle), the center of the focus might be placed at the boundary of thevein and the artery.

Once the transducers are energized 4550 after the region is targeted,the tissue is heated 4560 and a technique such as MRI thermography 4570or ultrasound thermography is utilized to determine the tissuetemperature. During the assessment of temperature, the anatomic datafrom the MRI scan or the Doppler ultrasound is then referenced to ensurethe proper degree of positioning and the degree of energy transductionis again further assessed by the modeling algorithm 4545 to set theparameters for the energy transducers 4550. If there is movement of thetarget, the transducers may have to be turned off and the patientrepositioned. Alternatively, the transducers can be redirected to adifferent position within the coordinate reference frame.

Ablation can also be augmented using agents such as magneticnanoparticles or liposomal nanoparticles which are responsive to aradiofrequency field generated by a magnet. These particles can beselectively heated by the magnetic field. The particles can also beenhanced such that they will target specific organs and tissues usingtargeting moieties such as antibodies, peptides, etc. In addition to thedelivery of heat, the particles can be activated to deliver drugs,bioactive agents, or imaging agents at the region at which action isdesired (e.g. the renal artery). The particles can be introduced via anintravenous route, a subcutaneous route, a direct injection routethrough the blood vessel, or a percutaneous route. As an example,magnetic nanoparticles or microparticles respond to a magnetic field bygenerating heat in a local region around them. Similarly, liposomalparticles might have a metallic particle within such that the magneticparticle heats up the region around the liposome but the liposome allowsaccurate targeting and biocompatibility.

The addition of Doppler ultrasound 4510 may be provided as well. Therenal arteries are (if renal arteries or regions surrounding thearteries are the target) placed in a 3D coordinate reference frame 4530using a software algorithm with or without the help of fiducial markers.Data is supplied to ultrasound transducers 4540 from a heat modelingalgorithm 4545 and the transducers are energized with the appropriatephase and power to heat the region of the renal artery to between 40° C.and 90° C. within a time span of several minutes. The position withinthe 3D coordinate reference is also integrated into the treatmentalgorithm so that the ultrasound transducers can be moved into theappropriate position. The ultrasound transducers may have frequenciesbelow 1 megahertz (MHz), from 1-20 MHz, or above 30 Mhz, or around 750kHz, 500 kHz, or 250 kHz. The transducers may be in the form of a phasedarray, either linear or curved, or the transducers may be mechanicallymoved so as to focus ultrasound to the target of interest. In addition,MRI thermography 4570 can be utilized so as to obtain the actualtemperature of the tissue being heated. These data can be further fedinto the system to slow down or speed up the process of ablation 4560via the transducers 4550.

Aside from focused ultrasound, ultrasonic waves can be utilized directlyto either heat an area or to activate pharmaceuticals in the region ofinterest. There are several methodologies to enhance drug delivery usingfocused ultrasound. For example, particles can release pharmaceuticalwhen they are heated by the magnetic field. Liposomes can release apayload when they are activated with focused ultrasound. Ultrasoundwaves have a natural focusing ability if a transducer is placed in thevicinity of the target and the target contains an activateable moietysuch as a bioactive drug or material (e.g. a nanoparticle sensitive toacoustic waves). Examples of sonodynamically activated moieties includesome porphyrin derivatives.

So as to test the region of interest and the potential physiologiceffect of ablation in that region, the region can be partially heated orvibrated with the focused ultrasound to stun or partially ablate thenerves. Next, a physiologic test such as the testing of blood pressureor measuring norepinephrine levels in the blood, kidney, blood vesselsleading to or from the kidney, can be performed to ensure that thecorrect region was indeed targeted for ablation. Depending on theparameter, additional treatments may be performed.

Clinically, this technique might be called fractionation of therapywhich underscores one of the major advantages of the technique to applyexternal energy versus applying internal energy to the renal arteries.An internal technique requires invasion through the skin and entry intothe renal artery lumens which is costly and potentially damaging.Patients will likely not accept multiple treatments, as they are highlyinvasive and painful. An external technique allows for a less invasivetreatment to be applied on multiple occasions, made feasible by the lowcost and minimal invasion of the technology described herein.

In another embodiment, a fiducial is utilized to demarcate the region ofinterest. A fiducial can be intrinsic (e.g. part of the anatomy) or thefiducial can be extrinsic (e.g. placed in position). For example, thefiducial can be an implanted fiducial, an intrinsic fiducial, or deviceplaced in the blood vessels, or a device placed percutaneously through acatheterization or other procedure. The fiducial can also be a bone,such as a rib, or another internal organ, for example, the liver. In oneembodiment, the fiducial is a beacon or balloon or balloon with a beaconwhich is detectable via ultrasound. In one embodiment, the blood flow inthe renal arteries, detected via Doppler or B-mode imaging, is thefiducial and its relative direction is determined via Doppler analysis.Next, the renal arteries, and specifically, the region around the renalarteries are placed into a three dimensional coordinate frame utilizingthe internal fiducials. A variant of global positioning systemtechnology can be utilized to track the fiducials within the artery oraround the arteries. In this embodiment, a position sensor is placed inthe artery or vein through a puncture in the groin. The position of thesensor is monitored as the sensor is placed into the blood vessel andits position in physical space relative to the outside of the patient,relative to the operator and relative to the therapeutic transducer istherefore known. The three dimensional coordinate frame is transmittedto the therapeutic ultrasound transducers and then the transducers andanatomy are coupled to the same coordinate frame. At this point, theHIFU is delivered from the transducers, calculating the position of thetransducers based on the position of the target in the reference frame.

In one embodiment, a virtual fiducial is created via an imaging system.For example, in the case of a blood vessel such as the renal artery, animage of the blood vessel using B-mode ultrasound can be obtained whichcorrelates to the blood vessel being viewed in direct cross section(1705; FIG. 17F). When the vessel is viewed in this type of view, thecenter of the vessel can be aligned with the center 1700 of anultrasound array (e.g. HIFU array 1600) and the transducers can befocused and applied to the vessel, applying heat lesions 1680 to regionsaround the vessel 1705. With different positions of the transducers 1610along a circumference or hemisphere 1650, varying focal points can becreated 1620, 1630, 1640. The directionality of the transducers allowsfor a lesion(s) 1620, 1630, 1640 which run lengthwise along the vessel1700. Thus, a longitudinal lesion 1620-1640 can be produced along theartery to insure maximal inhibition of nerve function. In someembodiments, the center of the therapeutic ultrasound transducer is offcenter relative to the center of the vessel so that the energy isapplied across the vessel wall at an angle, oblique to the vessel.

In this method of treatment, an artery such as a renal artery is viewedin cross-section or close to a cross-section under ultrasound guidance.In this position, the blood vessel is substantially parallel to the axisof the spherical transducer so as to facilitate lesion production. Thesetup of the ultrasound transducers 1600 has previously been calibratedto create multiple focal lesions 1620, 1630, 1640 along the artery ifthe artery is in cross-section 1680.

In one embodiment, the fiducial is an intravascular fiducial such as aballoon or a hermetically sealed transmitting device. The balloon isdetectable via radiotransmitter within the balloon which is detectableby the external therapeutic transducers. The balloon can have threetransducers, each capable of relaying its position so that the ballooncan be placed in a three dimensional coordinate reference. Once theballoon is placed into the same coordinate frame as the externaltransducers using the transmitting beacon, the energy transducingdevices can deliver energy (e.g. focused ultrasound) to the blood vessel(e.g. the renal arteries) or the region surrounding the blood vessels(e.g. the renal nerves). The balloon and transmitters also enable theability to definitively track the vasculature in the case of movement(e.g. the renal arteries). In another embodiment, the balloon measurestemperature or is a conduit for coolant applied during the heating ofthe artery or nerves.

Delivery of therapeutic ultrasound energy to the tissue inside the bodyis accomplished via the ultrasound transducers which are directed todeliver the energy to the target in the coordinate frame.

Once the target is placed in the coordinate frame and the energydelivery is begun, it is important to maintain targeting of theposition, particularly when the target is a small region such as thesympathetic nerves. To this end, the position of the region of ablationis compared to its baseline position, both in a three dimensionalcoordinate reference frame. The ongoing positional monitoring andinformation is fed into an algorithm which determines the new targetingdirection of the energy waves toward the target. In one embodiment, ifthe position is too far from the original position (e.g. the patientmoves), then the energy delivery is stopped and the patientrepositioned. If the position is not too far from the original position,then the energy transducers can be repositioned either mechanically(e.g. through physical movement) or electrically via phased array (e.g.by changing the relative phase of the waves emanating from thetransducers). In another embodiment, multiple transducers are placed onthe patient in different positions and each is turned on or off toresult in the necessary energy delivery. With a multitude of transducersplaced on the patient, a greater territory can be covered with thetherapeutic ultrasound. The therapeutic positions can also serve asimaging positions for intrinsic and/or extrinsic fiducials.

In addition to heat delivery, ultrasound can be utilized to delivercavitating energy which may enable drug delivery at certain frequencies.Cavitating energy can also lead to ablation of tissue at the area of thefocus. A systemic dose of a drug can be delivered to the region ofinterest and the region targeted with the cavitating or other forms ofultrasonic energy. Other types of therapeutic delivery modalitiesinclude ultrasound sensitive bubbles or radiation sensitivenanoparticles, all of which enhance the effect of the energy at thetarget of interest.

FIG. 7E depicts the anatomy of the region 4600, the kidneys 4620, renalarteries 4630, and bony structures 4610, 4640 as viewed from behind ahuman patient. FIG. 7E depicts the real world placement of the renalarteries into coordinate frame as outlined in FIG. 7D. Cross sectionalCT scans from actual human patients were integrated to create athree-dimensional representation of the renal artery, kidney, andmid-torso region. Plane 4623 is a plane parallel to the transverseprocesses and angle 4607 is the angle one has to look up in order to“see” the renal artery under the rib.

FIG. 7F depicts an image of the region of the renal arteries and kidney4605 using ultrasound. The renal hilum containing the arteries and vein4640 can be visualized using this imaging modality. This image istypical when looking at the kidney and renal artery from the directionand angle depicted in FIG. 7E. Importantly, at the angle 4607 in 7E,there is no rib in the ultrasound path and there no other importantstructures in the path either.

An ultrasound imaging trial was then performed to detect the availablewindows to deliver therapeutic ultrasound to the region of the renalarteries 4630 from the posterior region of the patient. It wasdiscovered that the window depicted by arrow 4600 and depicted by arrow4605 in the cross-sectional ultrasound image from ultrasound (FIG. 7F)provided optimal windows to visualize the anatomy of interest (renalpedicle 4640).

FIG. 7G contains some of the important data from the trial 4700, thedata in the “standard position 4730.” These data 4720 can be used todetermine the configuration of the clinical HIFU system to deliverultrasound to the renal hilum. The renal artery 4635 was determined tobe 7-17 cm from the skin in the patients on average. The flank toposterior approach was noted to be optimum to image the renal artery,typically through the parenchyma of the kidney as shown in FIG. 7F 4605.The hilum 4640 of the kidney is approximately 4-8 cm from the ultrasoundtransducer and the angle of approach 4637 (4607 in FIG. 7E) relative toan axis defined by the line connecting the two spinous processes andperpendicular to the spine . . . is approximately −10 to −48 degrees. Itwas also noted that the flank approach through the kidney was the safestapproach in that it represents the smallest chances of applyingultrasound to other organs such as bowel.

Upon further experimentation, it was discovered that by positioning thepatient in the prone position (backside up, abdomen down), thestructures under study 4750 . . . that is, the renal arteries 4770 and4780, the kidney hilum were even closer to the skin and the respiratorymotion of the artery and kidney was markedly decreased. FIG. 7H depictsthese results 4750, 4760 showing the renal artery 4770 at 6-10 cm andthe angle of approach 4790 relative to the spine 4607 shallower at −5 to−20 degrees.

Therefore, with these clinical data, in one embodiment, a method oftreatment 4800 (FIG. 7I) of the renal nerves in a patient has beendevised: 1) identify the rib 4810 and iliac crest 4840 of a patient onthe left and right flank of the patient 4810; 2) identify the left orright sided kidney with ultrasound 4820; 3) identify the hilum of thekidney and the extent the renal hilum is visible along surface ofpatient 4820 using an imaging technology; 4) identify the blood vesselsleading to the kidney from one or more angles, extracting the extent ofvisibility 4860 along the surface area of the patient's back; 5)determine the distance to the one or more of the renal artery, renalvein, kidney, and the renal hilum 4850; 6) optionally, position patientin the prone position with a substantive positioning device underneaththe back of the patient or overtop the abdomen of the patient 4830, tooptimize visibility; 7) optionally determine, through modeling, therequired power to obtain a therapeutic dose at the renal hilum andregion around the renal blood vessels; 8) apply therapeutic energy torenal blood vessels; 9) optionally track the region of the blood vesselsto ensure the continued delivery of energy to the region as planned inthe modeling; 10) optionally, turning off delivery of energy in the casethe focus of the energy is outside of the planned region.

FIG. 8A depicts a percutaneous procedure and device 5010 in which theregion around the renal artery 5030 is directly approached through theskin from an external position. A combination of imaging and applicationof energy (e.g. ablation) may be performed to ablate the region aroundthe renal artery to treat hypertension, end stage renal disease, andheart failure. Probe 5010 is positioned through the skin and inproximity to the kidney 5030. The probe may include sensors at its tip5020 which detect heat or temperature or may enable augmentation of thetherapeutic energy delivery. Ablative, ionizing energy, heat, or lightmay be applied to the region to inhibit the sympathetic nerves aroundthe renal artery using the probe 5010. Ultrasound, radiofrequency,microwave, direct heating elements, and balloons with heat or energysources may be applied to the region of the sympathetic nerves. Imagingmay be included on the probe or performed separately while the probe isbeing applied to the region of the renal blood vessels.

In one embodiment, the percutaneous procedure in FIG. 8A is performedunder MRI, CT, or ultrasound guidance to obtain localization orinformation about the degree of heat being applied. In one embodiment,ultrasound is applied but at a sub-ablative dose. That is, the energylevel is enough to damage or inhibit the nerves but the temperature issuch that the nerves are not ablated but paralyzed or partiallyinhibited by the energy. A particularly preferred embodiment would be toperform the procedure under guidance from an MRI scanner because theregion being heated can be determined anatomically in real time as wellvia temperature maps. As described above, the images after heating canbe compared to those at baseline and the signals are compared at thedifferent temperatures.

In one embodiment, selective regions of the kidney are ablated throughthe percutaneous access route; for example, regions which secretehormones which are detrimental to a patient or to the kidneys or otherorgans. Using energy applied externally to the patient through the skinand from different angles affords the ability to target any region in oron the kidney or along the renal nerves or at the region of the adrenalgland, aorta, or sympathetic chain. This greater breadth in the numberof regions to be targeted is enabled by the combination of externalimaging and external delivery of the energy from a multitude of anglesthrough the skin of the patient and to the target. The renal nerves canbe targeted at their takeoff from the aorta onto the renal artery, attheir synapses at the celiac ganglia, or at their bifurcation pointalong the renal artery.

In a further embodiment, probe 5010 can be utilized to detecttemperature or motion of the region while the ultrasound transducers areapplying the energy to the region. A motion sensor, position beacon, oraccelerometer can be used to provide feedback for the HIFU transducers.In addition, an optional temperature or imaging modality may be placedon the probe 5010. The probe 5010 can also be used to locate theposition within the laparoscopic field for the ablations to beperformed. The dose delivered by this probe is approximately

In FIG. 8B, intravascular devices 5050, 5055 are depicted which applyenergy to the region around the renal arteries 5065 from within therenal arteries. The intravascular devices can be utilized to applyradiofrequency, ionizing radiation, and/or ultrasound (either focused orunfocused) energy to the renal artery and surrounding regions. MRI orultrasound or direct thermometry can be further utilized to detect theregion where the heat is being applied while the intravascular catheteris in place.

In one embodiment, devices 5050, 5055 (FIG. 8B) apply ultrasound energywhich inhibits nerve function not by heating, but by mechanisms such asperiodic pressure changes, radiation pressure, streaming or flow inviscous media, and pressures associated with cavitation, defined as theformation of holes in liquid media. Heat can selectively be added tothese energies but not to create a temperature which ablates the nerves,only facilitates the mechanism of vibration and pressure. In thisembodiment, the ultrasound is not focused but radiates outward from thesource to essentially create a cylinder of ultrasonic waves thatintersect with the wall of the blood vessel. An interfacial materialbetween the ultrasound transducer and the wall of the artery may beprovided such that the ultrasound is efficiently transducted through thearterial wall to the region of the nerves around the artery. In anotherembodiment, the ultrasound directly enters the blood and propagatesthrough the ultrasound wall to affect the nerves. In some embodiments,cooling is provided around the ultrasound catheter which protects theinside of the vessel yet allows the ultrasound to penetrate through thewall to the regions outside the artery. A stabilization method for theultrasound probe is also included in such a procedure. The stabilizationmethod might include a stabilizing component added to the probe and mayinclude a range finding element component of the ultrasound so that theoperator knows where the ultrasound energy is being applied.

Imaging can be performed externally or internally in this embodiment inwhich a catheter is placed inside the renal arteries. For example,external imaging with MRI or Ultrasound may be utilized to visualizechanges during the ultrasound modulation of the nerve bundles. Indeed,these imaging modalities may be utilized for the application of any typeof energy within the wall of the artery. For example, radiofrequencydelivery of energy through the wall of the renal artery may be monitoredthrough similar techniques. Thus the monitoring of the proceduralsuccess of the technique is independent of the technique in most cases.

Alternatively, in another embodiment, the devices 5050, 5055 can beutilized to direct externally applied energy (e.g. ultrasound) to thecorrect place around the artery as the HIFU transducers deliver theenergy to the region. For example, the intravascular probe 5050 can beutilized as a homing beacon for the imaging/therapeutic technologyutilized for the externally delivered HIFU.

FIG. 8C depicts a percutaneous procedure to inhibit the renalsympathetic nerves. Probe 5010 is utilized to approach the renal hilum5060 region from posterior and renal artery 5065. With the datapresented below, the probe can be armed with HIFU to denvervate theregion. The data presented below indicates the feasibility of thisapproach as far as ultrasound enabling denervation of the vesselsquickly and easily.

In another embodiment, the physiologic process of arterial expansion(aneurysms) is targeted. In FIG. 9 a, an ultrasound transducer is 6005is placed near the wall of an aneurysm 6030. Ultrasonic energy 6015 isapplied to the wall 6030 of the aneurysm to thicken the wall and preventfurther expansion of the aneurysm. In some embodiments, clot within theaneurysm is targeted as well so that the clot is broken up or dissolvedwith the ultrasonic energy. Once the wall of the aneurysm is heated withultrasonic energy to a temperature of between 40 and 70 degrees, thecollagen, elastin, and other extracellular matrix in the wall willharden as it cools, thereby preventing the wall from further expansion.

In another embodiment, a material is placed in the aneurysm sac and thefocused or non-focused ultrasound utilized to harden or otherwise inducethe material in the sac to stick to the aorta or clot in the aneurysmand thus close the aneurysm permanently. In one embodiment therefore, anultrasound catheter is placed in an aorta at the region of an aneurysmwall or close to a material in an aneurysmal wall. The material can be aman-made material placed by an operator or it can be material such asthrombus which is in the aneurysm naturally. Ultrasound is applied tothe wall, or the material, resulting in hardening of the wall or of thematerial, strengthening the aneurysm wall and preventing expansion. Theenergy can also be applied from a position external to the patient orthrough a percutaneously positioned energy delivering catheter.

FIG. 9 b 6000 depicts a clot prevention device 6012 (vena cava filter)within a blood vessel such as the aorta or vena cava 6010. Theultrasound catheter 6005 is applied to the clot prevention device(filter) 6012 so as to remove the clot from the device or to free thedevice 6012 from the wall of the blood vessel in order to remove it fromthe blood vessel 6000.

FIG. 9 c depicts a device and method in which the celiac plexus 6020close to the aorta 6000 is ablated or partially heated using heat orvibrational energy from an ultrasonic energy source 6005 which can applyfocused or unfocused sound waves 6007 at frequencies ranging from 20kilohertz to 5 Mhz and at powers ranging from 1 mW to over 100 kW in afocused or unfocused manner. Full, or partial ablation of the celiacplexus 6020 can result in a decrease in blood pressure via a similarmechanism as applying ultrasonic energy to the renal nerves; theablation catheter is a focused ultrasound catheter but can also be adirect (unfocused) ultrasonic, a microwave transducer, or a resistiveheating element. Energy can also be delivered from an external positionthrough the skin to the aorta or celiac plexus region.

FIG. 10 depicts a method 6100 to treat a patient with high intensity orlow intensity focused ultrasound (HIFU or LIFU) 6260. In a first step, aCT and/or MRI scan and/or thermography and/or ultrasound (1D, 2D, 3D) isperformed 6110. A fiducial or other marking on or in the patient 6120 isoptionally used to mark and track 6140 the patient. The fiducial can bean implanted fiducial, a temporary fiducial placed internally orexternally in or on the patient, or a fiducial intrinsic to the patient(e.g. bone, blood vessel, arterial wall) which can be imaged using theCT/MRI/Ultrasound devices 6110. The fiducial can further be a temporaryfiducial such as a catheter temporarily placed in an artery or vein of apatient or a percutaneously placed catheter. A planning step 6130 forthe HIFU treatment is performed in which baseline readings such asposition of the organ and temperature are determined; a HIFU treatmentis then planned using a model (e.g. finite element model) to predictheat transfer, or pressure to heat transfer, from the ultrasoundtransducers 6130. The planning step incorporates the information on thelocation of the tissue or target from the imaging devices 6110 andallows placement of the anatomy into a three dimensional coordinatereference such that modeling 6130 can be performed.

The planning step 6130 includes determination of the positioning of theultrasound transducers as far as position of the focus in the patient.X,Y,Z, and up to three angular coordinates are used to determine theposition of the ultrasonic focus in the patient based on the crosssectional imaging 6110. The HIFU transducers might have their ownposition sensors built in so that the position relative to the targetcan be assessed. Alternatively, the HIFU transducers can be rigidlyfixed to the table on which the patient rests so that the coordinatesrelative to the table and the patient are easily obtainable. The flow ofheat is also modeled in the planning step 6130 so that the temperatureat a specific position with the ultrasound can be planned and predicted.For example, the pressure wave from the transducer is modeled as itpenetrates through the tissue to the target. For the most part, thetissue can be treated as water with a minimal loss due to interfaces.Modeling data predicts that this is the case. The relative power andphase of the ultrasonic wave at the target can be determined by thepositional coupling between the probe and target. A convective heattransfer term is added to model heat transfer due to blood flow,particularly in the region of an artery. A conductive heat transfer termis also modeled in the equation for heat flow and temperature.

Another variable which is considered in the planning step is the size ofthe lesion and the error in its position. In the ablation of smallregions such as nerves surrounding blood vessels, the temperature of theregions may need to be increased to a temperature of 60-90 degreesCelsius to permanently ablate nerves in the region. Temperatures of40-60 degrees may temporarily inhibit or block the nerves in theseregions and these temperatures can be used to determine that a patientwill respond to a specific treatment without permanently ablating thenerve region. Subsequently, additional therapy can be applied at a latertime so as to complete the job or perhaps, re-inhibit the nerve regions.

An error analysis is also performed during the treatment contemplated inFIG. 10. Each element of temperature and position contains an errorvariable which propagates through the equation of the treatment. Theerrors are modeled to obtain a virtual representation of the temperaturemapped to position. This map is correlated to the position of theultrasound transducers in the treatment of the region of interest.

During the delivery of the treatment 6260, the patient may move, inwhich case the fiducials 6120 track the movement and the position of thetreatment zone is re-analyzed 6150 and the treatment is restarted or thetransducers are moved either mechanically or electrically to a new focusposition.

In another embodiment, a cross-sectional technique of imaging is used incombination with a modality such as ultrasound to create a fusion typeof image. The cross-sectional imaging is utilized to create a threedimensional data set of the anatomy. The ultrasound, providing twodimensional images, is linked to the three dimensional imaging providedby the cross-sectional machine through fiducial matches between theultrasound and the MRI. As a body portion moves within the ultrasoundfield, the corresponding data is determined (coupled to) thecross-sectional (e.g. MRI image) and a viewing station can show themovement in the three dimensional dataset. The ultrasound provides realtime images and the coupling to the MRI or other cross-sectional imagedepicts the ultrasound determined position in the three dimensionalspace.

FIG. 11 depicts the treatment 7410 of another disease in the body of apatient, this time in the head of a patient. Subdural and epiduralhematomas occur as a result of bleeding of blood vessels in the dural orepidural spaces of the brain, spinal column, and scalp. FIG. 11 depictsa CT or MRI scanner 7300 and a patient 7400 therein. An image isobtained of the brain 7000 using a CT or MRI scan. The image is utilizedto couple the treatment zone 7100 to the ultrasound array utilized toheat the region. In one embodiment 7100, a subdural hematoma, eitheracute or chronic, is treated. In another embodiment 7200, an epiduralhematoma is treated. In both embodiments, the region of leakingcapillaries and blood vessels are heated to stop the bleeding, or in thecase of a chronic subdural hematoma, the oozing of the inflammatorycapillaries.

In an exemplary embodiment of modulating physiologic processes, apatient 7400 with a subdural or epidural hematoma is chosen fortreatment and a CT scan or MRI 7300 is obtained of the treatment region.Treatment planning ensues and the chronic region of the epidural 7200 orsub-dural 7010 hematoma is targeted for treatment with the focusedultrasound 7100 transducer technology. Next the target of interest isplaced in a coordinate reference frame as are the ultrasoundtransducers. Therapy 7100 ensues once the two are coupled together. Thefocused ultrasound heats the region of the hematoma to dissolve the clotand/or stop the leakage from the capillaries which lead to theaccumulation of fluid around the brain 7420. The technology can be usedin place of or in addition to a burr hole, which is a hole placedthrough the scalp to evacuate the fluid.

FIG. 12 depicts a laparoscopic based approach 8000 to the renal arteryregion in which the sympathetic nerves 8210 can be ligated, interrupted,or otherwise modulated. In laparoscopy, the abdomen of a patient isinsufflated and laparoscopic instruments introduced into the insufflatedabdomen. The retroperitoneum is easily accessible through a flankapproach or (less so) through a transabdominal (peritoneal) approach. Alaparoscopic instrument 8200 with a distal tip 8220 can apply heat oranother form of energy or deliver a drug to the region of thesympathetic nerves 8210. The laparoscopic instrument can also beutilized to ablate or alter the region of the celiac plexus 8300 andsurrounding ganglia. The laparoscope can have an ultrasound transducer8220 attached, a temperature probe attached, a microwave transducerattached, or a radiofrequency transducer attached. The laparoscope canbe utilized to directly ablate or stun the nerves (e.g. with a lowerfrequency/energy) surrounding vessels or can be used to ablate or stunnerve ganglia which travel with the blood vessels. Similar types ofmodeling and imaging can be utilized with the percutaneous approach aswith the external approach to the renal nerves. With the discoverythrough animal experimentation (see below) that a wide area of nerveinhibition can be affected with a single ultrasound probe in a singledirection (see above), the nerve region does not have to be directlycontacted with the probe, the probe instead can be directed in thegeneral direction of the nerve regions and the ultrasound delivered. Forexample, the probe can be placed on one side of the vessel and activatedto deliver focused or semi-focused ultrasound over a generalized regionwhich might not contain greater than 1 cm of longitudinal length of theartery but its effect is enough to completely inhibit nerve functionalong.

FIG. 13 depicts an algorithm 8400 for the treatment of a region ofinterest using directed energy from a distance. MRI and/or CT with orwithout an imaging agent 8410 can be utilized to demarcate the region ofinterest (for example, the ablation zone) and then ablation 8420 can beperformed around the zone identified by the agent using any of themodalities above. This algorithm is applicable to any of the therapeuticmodalities described above including external HIFU, laparoscopicinstruments, intravascular catheters, percutaneous catheters andinstruments, as well as any of the treatment regions including the renalnerves, the eye, the kidneys, the aorta, or any of the other nervessurrounding peripheral arteries or veins. Imaging 8430 with CT, MRI,ultrasound, or PET can be utilized in real time to visualize the regionbeing ablated. At such time when destruction of the lesion is complete8440, imaging with an imaging (for example, a molecular imaging agent ora contrast agent such as gadolinium) agent 8410 can be performed again.The extent of ablation can also be monitored by monitoring thetemperature or the appearance of the ablated zone under an imagingmodality. Once lesion destruction is complete 8440, the procedure isfinished. In some embodiments, ultrasonic diagnostic techniques such aselastography are utilized to determine the progress toward heating orablation of a region.

FIG. 14 depicts ablation in which specific nerve fibers of a nerve aretargeted using different temperature gradients, power gradients, ortemperatures 8500. For example, if temperature is determined by MRIthermometry or with another technique such as ultrasound, infraredthermography, or a thermocouple, then the temperature can be kept at atemperature in which only certain nerve fibers are targeted fordestruction or inhibition. Alternatively, part or all of the nerve canbe turned off temporarily to then test the downstream effect of thenerve being turned off. For example, the sympathetic nerves around therenal artery can be turned off with a small amount of heat or otherenergy (e.g. vibrational energy) and then the effect can be determined.For example, norepinephrine levels in the systemic blood, kidney, orrenal vein can be assayed; alternatively, the stimulation effect of thenerves can be tested after temporary cessation of activity (e.g. skinreactivity, blood pressure lability, cardiac activity, pulmonaryactivity, renal artery constriction in response to renal nervestimulation). For example, in one embodiment, the sympathetic activitywithin a peripheral nerve is monitored; sympathetic activity typicallymanifests as spikes within a peripheral nerve electrical recording. Thenumber of spike correlates with the degree of sympathetic activity orover-activity. When the activity is decreased by (e.g. renal arteryde-inervation), the concentration of spikes in the peripheral nervetrain is decreased, indicating a successful therapy of the sympatheticor autonomic nervous system. Varying frequencies of vibration can beutilized to inhibit specific nerve fibers versus others. For example, insome embodiments, the efferent nerve fibers are inhibited and in otherembodiments, the afferent nerve fibers are inhibited. In someembodiments, both types of nerve fibers are inhibited, temporarily orpermanently. In some embodiments, the C fibers 8520 are selectivelyblocked at lower heat levels than the A nerve fibers. In otherembodiment, the B fibers are selectively treated or blocked and in someembodiments, the A fibers 8530 are preferentially blocked. In someembodiments, all fibers are inhibited by suturing the nerve with a highdose of ultrasound 8510. Based on the experimentation described above,the power density to achieve full blockage might be around 100-800 W/cm²or with some nerves from about 500 to 2500 W/cm². In some embodiments, apulse train of 100 or more pulses each lasting 1-2 seconds (for example)and delivering powers from about 50 w/cm² to 500 W/cm². Indeed, priorliterature has shown that energies at or about 100 W/Cm² is adequate todestroy or at least inhibit nerve function (Lele, PP. Effects of FocusedUltrasound Radiation on Peripheral Nerve, with Observations on LocalHeating. Experimental Neurology 8, 47-83 1963 incorporated byreference).

FIG. 15 a depicts treatment 8600 of a vertebral body or intervertebraldisk 8610 in which nerves within 8640 or around the vertebral column8630 are targeted with energy 8625 waves. In one embodiment, nervesaround the facet joints are targeted. In another embodiment, nervesleading to the disks or vertebral endplates are targeted. In anotherembodiment, nerves within the vertebral bone 8630 are targeted byheating the bone itself. Sensory nerves run through canals 8635 in thevertebral bone 8630 and can be inhibited or ablated by heating the bone8630.

FIG. 15B depicts a close-up of the region of the facet joint. Focusedultrasound to this region can inhibit nerves involved in back pain whichoriginate at the dorsal root nerve and travel to the facet joint 8645.Ablation or inhibition of these nerves can limit or even cure back paindue to facet joint arthropathy. Focused ultrasound can be applied to theregion of the facet joint from a position outside the patient to thefacet joint using powers of between 100 W/cm² and 2500 W/cm² at thenerve from times ranging from 1 second to 10 minutes.

FIG. 16A depicts a set of lesion types, sizes, and anatomies 8710 a-fwhich lead to de-innervation of the different portions of thesympathetic nerve tree around the renal artery. For example, the lesionscan be annular, cigar shaped, linear, doughnut and/or spherical; thelesions can be placed around the renal arteries 8705, inside the kidney8710, and/or around the aorta 8700. For example, the renal arterial treecomprises a portion of the aorta 8700, the renal arteries 8705, andkidneys 8715. Lesions 8714 and 8716 are different types of lesions whichare created around the aorta 8700 and vascular tree of the kidneys.Lesions 8712 and 8718 are applied to the pole branches from the renalartery leading to the kidney and inhibit nerve functioning at branchesfrom the main renal artery. These lesions also can be applied from aposition external to the patient. Lesions can be placed in a spiralshape 8707 along the length of the artery as well. These lesions can beproduced using energy delivered from outside the blood vessels using acompletely non-invasive approach in which the ultrasound is appliedthrough the skin to the vessel region or the energy can be delivered viapercutaneous approach. Either delivery method can be accomplishedthrough the posterior approach to the blood vessels as discovered anddescribed above.

In one method therefore, ultrasound energy can be applied to the bloodvessel leading to a kidney in a pattern such that a circular pattern ofheat and ultrasound is applied to the vessel. The energy is transmittedthrough the skin in one embodiment or through the artery in anotherembodiment. As described below, ultrasound is transmitted from adistance and is inherently easier to apply in a circular pattern becauseit doesn't only rely on conduction.

Previously, it was unknown and undiscovered whether or not the annularshaped lesions as shown in FIG. 16 a would have been sufficient to blocknerve function of the autonomic nerves around the blood vessels.Applicant of the subject application discovered that the annular shapedablations 8710 not only block function but indeed completely block nervefunction around the renal artery and kidney and with very minimal damage(FIG. 16C), if any, to the arteries and veins themselves. In theseexperiments, focused ultrasound was used to block the nerves; theultrasound was transmitted through and around the vessel from the top(that is, only one side of the vessel) at levels of 200-2500 W/cm².Simulations are shown in FIG. 16B and described below. Norepinephrinelevels in the kidney 8780, which are utilized to determine the degree ofnerve inhibition, were determined before and after application ofenergy. The lower the levels of norepinephrine, the more nerves whichhave been inhibited. In these experiments which were performed, thenorepinephrine levels approached zero 8782 versus controls 8784 whichremained high. In fact, the levels were equal to or lower than thesurgically denuded blood vessels (surgical denudement involves directlycutting the nerves surgically). It is important that the renal arteryand vein walls were remained substantially unharmed; this is likely dueto the fact that the quick arterial blood flow removes heat from thevessel wall and the fact that the main renal artery is extremelyresilient due to its large size, high blood flow, and thick wall. Tosummarize, ultrasound (focused and relatively unfocused) was applied toone side of the renal artery and vein complex. The marker of nerveinhibition, norepinephrine levels inside the kidney, were determined tobe approaching zero after application to the nerves from a singledirection, transmitting the energy through the artery wall to reachnerves around the circumference of the artery. The level of zeronorepinephrine 8782 indicates essentially complete abolition of nervefunction proving that the annular lesions were in fact created asdepicted in FIG. 16A and simulated in FIG. 16B. Histological resultsalso confirm the annular nature of the lesions and limited collateraldamage as predicted by the modeling in 16B.

Therefore, in one embodiment, the ultrasound is applied from a positionexternal to the artery in such a manner so as to create an annular orsemi-annular rim of heat all the way around the artery to inhibit,ablate, or partially ablate the autonomic nerves surrounding the artery.The walls or the blood flow of the artery can be utilized to target theultrasound to the nerves which, if not directly visualized, arevisualized by use of a model to approximate the position of the nervesbased on the position of the blood vessel.

FIG. 16B further supports the physics and physiology described herein,depicting a theoretical simulation 8750 of the physical and animalexperimentation described above. That is, focused ultrasound wastargeted to a blood vessel in a computer simulation 8750. The renalartery 8755 is depicted within the heating zone generated within afocused ultrasound field. Depicted is the temperature at <1 s 8760 andat approximately 5 s 8765 and longer time >10 s 8767. Flow direction8770 is shown as well. The larger ovals depict higher temperatures withthe central temperature >100° C. The ultrasound field is transmittedthrough the artery 8755, with heat building up around the artery asshown via the temperature maps 8765. Importantly, this theoreticalsimulation also reveals the ability of the ultrasound to travel throughthe artery and affect both walls of the blood vessel. These data areconsistent with the animal experimentation described above, creating aunified physical and experimental dataset.

Therefore, based on the animal and theoretical experimentation, there isproven feasibility of utilizing ultrasound to quickly and efficientlyinhibit the nerves around the renal arteries from a position external tothe blood vessels as well as from a position external to the skin of thepatient.

Utilizing the experimental simulations and animal experimentationdescribed above, a clinical device can and has been devised and testedin human patients. FIG. 17A depicts a multi-transducer HIFU device 1100which applies a finite lesion 1150 along an artery 1140 (e.g. a renalartery) leading to a kidney 1130. The lesion can be spherical in shape,cigar shaped 1150, annular shaped 8710 (FIG. 16A), or point shaped;however, in a preferred embodiment, the lesion runs along the length ofthe artery and has a cigar shaped 1150. This lesion is generated by aspherical or semi-spherical type of ultrasound array in a preferredembodiment. Multiple cigar shaped lesion as shown in FIG. 17C leads to aring type of lesion 1350.

FIG. 17B depicts an imaging apparatus display which monitors treatment.Lesion 1150 is depicted on the imaging apparatus as is the aorta 1160and renal artery 1155. The image might depict heat, tissue elastography,vibrations, or might be based on a simulation of the position of thelesion 1150. FIG. 17C depicts another view of the treatment monitoring,with the renal artery in cross section 1340. Lesion 1350 is depicted incross section in this image as well. The lesion 1350 might be consideredto circumscribe the vessel 1340 in embodiments where multiple lesionsare applied.

FIG. 17D depicts a methodology 1500 to analyze and follow the deliveryof therapeutic focused ultrasound to an arterial region. A key step isto first position 1510 the patient optimally to image the treatmentregion; the imaging of the patient might involve the use of Dopplerimaging, M mode imaging, A scan imaging, or even MRI or CT scan. Theimaging unit is utilized to obtain coordinate data 1530 from the dopplershift pattern of the artery. Next, the focused ultrasound probe ispositioned 1520 relative to the imaged treatment region 1510 andtreatment can be planned or applied.

FIG. 17E depicts the pathway of the acoustic waves from a spherical orcylindrical type of ultrasound array 1600. In some embodiments, thetransducer is aspherical such that a sharp focus does not exist butrather the focus is more diffuse in nature or off the central axis.Alternatively, the asphericity might allow for different pathlengthsalong the axis of the focusing. For example, one edge of the ultrasoundtransducer might be called upon for 15 cm of propagation while anotheredge of the transducer might be called upon to propagate only 10 cm, inwhich case a combination of difference frequencies or angles might berequired.

Ultrasound transducers 1610 are aligned along the edge of a cylinder1650, aimed so that they intersect at one or more focal spots 1620,1630, 1640 around the vessel (e.g. renal artery). The transducers 1610are positioned along the cylinder or sphere or spherical approximation(e.g. aspherical) 1650 such that several of the transducers are closerto one focus or the other such that a range of distances 1620, 1630,1640 to the artery is created. The patient and artery are positionedsuch that their centers 1700 co-localize with the center of theultrasound array 1600. Once the centers are co-localized, the HIFUenergy can be activated to create lesions along the length of the arterywall 1640, 1620, 1630 at different depths and positions around theartery. The natural focusing of the transducers positioned along acylinder as in FIG. 17E is a lengthwise lesion, longer than in thicknessor height, which will run along the length of an artery 1155 when theartery 1340 is placed along the center axis of the cylinder. When viewedalong a cross section (FIG. 17F), the nerve ablations are positionedalong a clock face 1680 around the blood vessel.

In another embodiment, a movement system for the transducers is utilizedso that the transducers move along the rim of the sphere or cylinder towhich they are attached. The transducers can be moved automatically orsemi-automatically, based on imaging or based on external positionmarkers. The transducers are independently controlled electrically butcoupled mechanically through the rigid structure.

Importantly, during treatment, a treatment workstation 1300 (FIG. 17C)gives multiple views of the treatment zone with both physical appearanceand anatomy 1350. Physical modeling is performed in order to predictlesion depth and the time to produce the lesion; this information is fedback to the ultrasound transducers 1100. The position of the lesion isalso constantly monitored in a three dimensional coordinate frame andthe transducer focus at lesions center 1150 in the context of monitoring1300 continually updated.

In some embodiments, motion tracking prevents the lesion or patient frommoving too far out of the treatment zone during the ablation. If thepatient does move outside the treatment zone during the therapy, thenthe therapy can be stopped. Motion tracking can be performed using theultrasound transducers, tracking frames and position or with transducersfrom multiple angles, creating a three dimensional image with thetransducers. Alternatively, a video imaging system can be used to trackpatient movements, as can a series of accelerometers positioned on thepatient which indicate movement.

FIG. 18 depicts a micro-catheter 8810 which can be placed into renalcalyces 8820; this catheter allows the operator to specifically ablateor stimulate 8830 regions of the kidney 8800. The catheter can be usedto further allow for targeting of the region around the renal arteriesand kidneys by providing additional imaging capability or by assistingin movement tracking or reflection of the ultrasound waves to create orposition the lesion. The catheter or device at or near the end of thecatheter may transmit signals outside the patient to direct an energydelivery device which delivers energy through the skin. Signalingoutside the patient may comprise energies such as radiofrequencytransmission outside the patient or radiofrequency from outside to theinside to target the region surrounding the catheter. The followingpatent and patent applications describe the delivery of ultrasound usinga targeting catheter within a blood vessel, and are expresslyincorporated by reference herein:

Ser. Nos. 11/583,569, 12/762,938, 11/583,656, 12/247,969, 10/633,726,09/721,526, 10/780,405, 09/747,310, 12/202,195, 11/619,996, 09/696,076

In one system 8800, a micro catheter 8810 is delivered to the renalarteries and into the branches of the renal arteries in the kidney 8820.A signal is generated from the catheter into the kidney and out of thepatient to an energy delivery system. Based on the generated signal, theposition of the catheter in a three dimensional coordinate reference isdetermined and the energy source is activated to deliver energy 8830 tothe region indicated by the microcatheter 8810.

In an additional embodiment, station keeping is utilized. Stationkeeping enables the operator to maintain the position of the externalenergy delivery device with respect to the movement of the operator ormovement of the patient. As an example, targeting can be achieved withthe energy delivery system and

The microcatheter may be also be utilized to place a flow restrictorinside the kidney (e.g. inside a renal vein) to “trick” the kidney intothinking its internal pressure is higher than it might be. In thisembodiment, the kidney generates signals to the central nervous systemto lower sympathetic output to target organs in an attempt to decreaseits perfusion pressure.

Alternatively, specific regions of the kidney might be responsible forhormone excretion or other factors which lead to hypertension or otherdetrimental effects to the cardiovascular system. The microcatheter cangenerate ultrasound, radiofrequency, microwave, or X-ray energy. Themicrocatheter can be utilized to ablate regions in the renal vein orintra-parenchymal venous portion as well. In some embodiments, ablationis not required but vibratory energy emanating from the probe isutilized to affect, on a permanent or temporary basis, themechanoreceptors or chemoreceptors in the location of the hilum of thekidney.

FIG. 19A depicts the application 8900 of energy to the region of therenal artery 8910 and kidney 8920 using physically separated transducers8930, 8931. Although two are shown, the transducer can be a singletransducer which is connected all along. The transducer(s) can bespherical or aspherical, they can be couple to an imaging transducerdirectly or indirectly where the imaging unit might be separated at adistance. In contrast to the delivery method of FIG. 17, FIG. 19Adepicts delivery of ultrasound transverse to the renal arteries and notlongitudinal to the artery. The direction of energy delivery is theposterior of the patient because the renal artery is the first vessel“seen” when traveling from the skin toward the anterior directionfacilitating delivery of the therapy. In one embodiment, the transducers8930, 8931 are placed under, or inferior to the rib of the patient orbetween the ribs of a patient; next, the transducers apply an ultrasoundwave propagating forward toward the anterior abdominal wall and imagethe region of the renal arteries and renal veins, separating them fromone another. In some embodiments, such delivery might be advantageous,if for example, a longitudinal view of the artery is unobtainable or afaster treatment paradigm is desirable. The transducers 8930, 8931communicate with one another and are connected to a computer model ofthe region of interest being imaged (ROI), the ROI based on an MRI scanperformed just prior to the start of the procedure and throughout theprocedure. Importantly, the transducers are placed posterior in thecross section of the patient, an area with more direct access to thekidney region. The angle between the imaging transducers can be as lowas 3 degrees or as great as 180 degrees depending on the optimalposition in the patient.

In another embodiment, an MRI is not performed but ultrasound isutilized to obtain all or part of the cross-sectional view in FIG. 19A.For example, 8930 might contain an imaging transducer as well as atherapeutic energy source (e.g. ionizing energy, HIFU, low energyfocused ultrasound, etc.)

FIG. 19B depicts an ultrasound image from a patient illustrating imagingof the region with patient properly positioned as described below. It isthis cross section that can be treated with image guided HIFU of therenal hilum region. The kidney 8935 is visualized in cross section andultrasound then travels through to the renal artery 8937 and vein 8941.The distance can be accurately measure 8943 with ultrasound (in thiscase 8 cm 8943). This information is useful to help model the deliveryof energy to the renal blood vessels.

FIG. 20 depicts an alternative method, system 9000 and device to ablatethe renal nerves 9015 or the nerves leading to the renal nerves at theaorta-renal artery ostium 9010. The intravascular device 9020 is placedinto the aorta 9050 and advanced to the region of the renal arteries9025. Energy is applied from the transducer 9020 and focused 9040 (inthe case of HIFU, LIFU, ionizing radiation) to the region of the takeoffof the renal arteries 9025 from the aorta 9050. This intravascular 9030procedure can be guided using MRI and/or MRI thermometry or it can beguided using fluoroscopy, ultrasound, or MRI. Because the aorta islarger than the renal arteries, the HIFU catheter can be placed into theaorta directly and cooling catheters can be included as well. Inaddition, in other embodiments, non-focused ultrasound can be applied tothe region around the renal ostium or higher in the aorta. Non-focusedultrasound in some embodiments may require cooling of the tissuessurrounding the probe using one or more coolants but in someembodiments, the blood of the aorta will take the place of the coolant,by its high flow rate; HIFU, or focused ultrasound, may not need thecooling because the waves are by definition focused from differentangles to the region around the aorta. The vena cava and renal veins canalso be used as a conduit for the focused ultrasound transducer todeliver energy to the region as well. In one embodiment, the vena cavais accessed and vibratory energy is passed through the walls of the venacava and renal vein to the renal arteries, around which the nerves tothe kidney travel. The veins, having thinner walls, allow energy to passthrough more readily.

FIG. 21 a-b depicts an eyeball 9100. Also depicted are the zonules ofthe eye 9130 (the muscles which control lens shape) and ultrasoundtransducer 9120. The transducer 9120 applies focused ultrasound energyto the region surrounding the zonules, or the zonules themselves, inorder to tighten them such that a presbyopic patient can accommodate andvisualize object up close. Similarly, heat or vibration applied to theciliary muscles, which then increases the outflow of aqueous humor atthe region of interest so that the pressure within the eye cannot buildup to a high level. The ultrasound transducer 9120 can also be utilizedto deliver drug therapy to the region of the lens 9150, ciliary body,zonules, intra-vitreal cavity, anterior cavity 9140, posterior cavity,etc.

In some embodiments (FIG. 21 b), multiple transducers 9160 are utilizedto treat tissues deep within the eye; the ultrasonic transducers 9170are focused on the particular region of the eye from multiple directionsso that tissues along the path of the ultrasound are not damaged by theultrasound and the focus region and region of effect 9180 is theposition where the waves meet in the eye. In one embodiment, thetransducers are directed through the pars plana region of the eye totarget the macula 9180 at the posterior pole 9175 of the eye. Thisconfiguration might allow for heat, vibratory stimulation, drugdelivery, gene delivery, augmentation of laser or ionizing radiationtherapy, etc. In certain embodiments, focused ultrasound is not requiredand generic vibratory waves are transmitted through the eye atfrequencies from 20 kHz to 10 MHz. Such energy may be utilized to breakup clots in, for example, retinal venous or arterial occlusions whichare creating ischemia in the retina. This energy can be utilized incombination with drugs utilized specifically for breaking up clots inthe veins of the retina.

FIG. 22 depicts a peripheral joint 9200 being treated with heat and/orvibrational energy. Ultrasound transducer 9210 emits waves toward theknee joint to block nerves 9260 just underneath the bone periostium92209250 or underneath the cartilage. Although a knee joint is depicted,it should be understood that many joints can be treated including smalljoints in the hand, intervertebral joints, the hip, the ankle, thewrist, and the shoulder. Unfocused or focused ultrasonic energy can beapplied to the joint region to inhibit nerve function reversibly orirreversibly. Such inhibition of nerve function can be utilized to treatarthritis, post-operative pain, tendonitis, tumor pain, etc. In onepreferred embodiment, vibratory energy can be utilized rather than heat.Vibratory energy applied to the joint nerves can inhibit theirfunctioning such that the pain fibers are inhibited.

FIG. 23 a-b depicts closure of a fallopian tube 9300 of a uterus 9320using externally applied ultrasound 9310 so as to prevent pregnancy. MRIor preferably ultrasound can be utilized for the imaging modality.Thermometry can be utilized as well so as to see the true ablation zonein real time. The fallopian tube 9300 can be visualized usingultrasound, MRI, CT scan or a laparoscope. Once the fallopian tube istargeted, external energy 9310, for example, ultrasound, can be utilizedto close the fallopian tube to prevent pregnancy. When heat is appliedto the fallopian tube, the collagen in the walls are heated and willswell, the walls then contacting one another and closing the fallopianpreventing full ovulation and therefore preventing pregnancy. Althoughthere is no doppler signal in the fallopian tube, the technology forvisualization and treatment is similar to that for an artery or otherduct. That is, the walls of the tube are identified and modeled, thenfocused ultrasound is applied through the skin to the fallopian tube toapply heat to the walls of the lumen of the fallopian tube.

In FIG. 23 b, a method is depicted in which the fallopian tubes arevisualized 9340 using MRI, CT, or ultrasound. HIFU 9350 is applied undervisualization with MRI or ultrasound. As the fallopian tubes are heated,the collagen in the wall is heated until the walls of the fallopian tubeclose off. At this point the patient is sterilized 9360. During thetreating time, it may be required to determine how effective the heatingis progressing. If additional heat is required, then additional HIFU maybe added to the fallopian tubes until there is closure of the tube andthe patient is sterilized 9360. Such is one of the advantages of theexternal approach in which multiple treatments can be applied to thepatient, each treatment closing the fallopian tubes further, the degreeof success then assessed after each treatment. A further treatment canthen be applied 9370.

In other embodiments, ultrasound is applied to the uterus or fallopiantubes to aid in pregnancy by improving the receptivity of the spermand/or egg for one another. This augmentation of conception can beapplied to the sperm and egg outside of the womb as well, for example,in a test tube in the case of extra-uterine fertilization.

FIG. 24 depicts a feedback algorithm to treat the nerves of theautonomic nervous system. It is important that there be an assessment ofthe response to the treatment afterward. Therefore, in a first step,modulation of the renal nerves 9400 is accomplished by any or several ofthe embodiments discussed above. An assessment 9410 then ensues, theassessment determining the degree of treatment effect engendered; if acomplete or satisfactory response is determined 9420, then treatment iscompleted. For example, the assessment 9410 might include determinationthrough microneurography, assessment of the carotid sinus reactivity(described above), heart rate variability, measurement of norepinephrinelevels, etc. With a satisfactory autonomic response, further treatmentmight not ensue or depending on the degree of response, additionaltreatments of the nerves 9430 may ensue.

FIG. 25 depicts a reconstruction of a patient from CT scan imagesshowing the position of the kidneys 9520 looking through the skin of apatient 9500. The ribs 9510 partially cover the kidney but do reveal awindow at the inferior pole 9530 of the kidney 9520. Analysis of many ofthese reconstructions has lead to clinical paradigm in which the ribs9510, pelvis 9420, and the vertebra 9440 are identified on a patient,the kidneys are identified via ultrasound and then renal arteries areidentified via Doppler ultrasound.

As shown in FIG. 26 a, once the ribs and vertebra are identified withthe Doppler ultrasound, an external energy source 9600 can be applied tothe region. Specifically, focused ultrasound (HIFU or LIFU) can beapplied to the region once these structures are identified and a lesionapplied to the blood vessels (renal artery and renal nerve) 9620 leadingto the kidney 9610. As described herein, the position of the ultrasoundtransducer 9600 is optimized on the posterior of the patient as shown inFIG. 26A. That is, with the vertebra, the ribs, and the iliac crestbordering the region where ultrasound is applied.

Based on the data above and specifically the CT scan anatomicinformation in FIG. 26A, FIG. 26B depicts a device and system 9650designed for treatment of this region (blood vessels in the hilum of thekidney) in a patient. It contains a 0.5-3 Mhz ultrasound imagingtransducer 9675 in its center and a cutout or attachment location of theultrasound ceramic (e.g. PZT) for the diagnostic ultrasound placement.It also contains a movement mechanism 9660 to control the therapeutictransducer 9670. The diagnostic ultrasound device 9675 is coupled to thetherapeutic device in a well-defined, known relationship. Therelationship can be defined through rigid or semi-rigid coupling or itcan be defined by electrical coupling such as through infrared,optical-mechanical coupling and/or electro-mechanical coupling. Alongthe edges of the outer rim of the device, smaller transducers 9670 canbe placed which roughly identify tissues through which the ultrasoundtravels. For example, simple and inexpensive one or two-dimensionaltransducers might be used so as to determine the tissues through whichthe ultrasound passes on its way to the target can be used for thetargeting and safety. From a safety perspective, such data is importantso that the ultrasound does not hit bone or bowel and that thetransducer is properly placed to target the region around the renalblood vessels. Also included in the system is a cooling system totransfer heat from the transducer to fluid 9662 running through thesystem. Cooling via this mechanism allows for cooling of the ultrasoundtransducer as well as the skin beneath the system. A further feature ofthe system is a sensor mechanism 9665 which is coupled to the system9650 and records movement of the system 9650 relative to a baseline or acoordinate nearby. In one embodiment, a magnetic sensor is utilized inwhich the sensor can determine the orientation of the system relative toa magnetic sensor on the system. The sensor 9665 is rigidly coupled tothe movement mechanism 9660 and the imaging transducer 9675. In additionto magnetic, the sensor might be optoelectric, acoustic, orradiofrequency based.

Furthermore, the face 9672 of the transducer 9670 is shaped such that isfits within the bony region described and depicted in FIG. 26A. Forexample, the shape might be elliptical or aspheric ro in some casesshperic. In addition, in some embodiments the ultrasound imaging enginemight not be directly in the center of the device and in fact might besuperior to the center and closer to the superior border of the face andcloser to the ribs, wherein the renal artery is visualized better withthe imaging probe 9675.

Given the clinical data as well as the devised technologies describedabove (e.g. FIG. 26A-B), FIG. 27 illustrates the novel treatment plan9700 to apply energy to the nerves around the renal artery with energydelivered from a position external to the patient.

In one embodiment, the patient is stabilized and/or positioned such thatthe renal artery and kidneys are optimally located 9710. Diagnosticultrasound 9730 is applied to the region and optionally, ultrasound isapplied from a second direction 9715. The positioning and imagingmaneuvers allow the establishment of the location of the renal artery,the hilum, and the vein 9720. A test dose of therapeutic energy 9740 canbe applied to the renal hilum region. In some embodiments, temperature9735 can be measured. This test dose can be considered a full dose ifthe treatment is in fact effective by one or more measures. Thesemeasures might be blood pressure 9770, decrease in sympathetic outflow(as measured by microneurography 9765), increase in parasympatheticoutflow, change in the caliber of the blood vessel 9755 or a decrease inthe number of spontaneous spikes in a microneurographic analysis in aperipheral nerve (e.g. peroneal nerve) 9765, or an MRI or CT scan whichreveals a change in the nervous anatomy 9760. In some embodiments,indices within the kidney are utilized for feedback. For example, theresistive index, a measure of the vasoconstriction in the kidneymeasured by doppler ultrasound is a useful index related to the renalnerve activity; for example, when there is greater autonomic activity,the resistive index increases, and vice versa.

Completion of the treatment 9745 might occur when the blood pressurereaches a target value 9770. In fact, this might never occur or it mayoccur only after several years and treatment. The blood pressure mightcontinually be too high and multiple treatments may be applied over aperiod of years . . . the concept of dose fractionation. Fractionationis a major advantage of applying energy from a region external to aregion around the renal arteries in the patient as it is more convenientand less expensive when compared to invasive treatments such stimulatorimplantation and interventional procedures such as catheterization ofthe renal artery.

Another important component is the establishment of the location andposition of the renal artery, renal vein, and hilum of the kidney 9720.As discussed above, the utilization of Doppler ultrasound signalingallows for the position of the nerves to be well approximated such thatthe ultrasound can be applied to the general region of the nerves. Theregion of the nerves can be seen in FIGS. 29A-D. FIGS. 29A-C aresketches from actual histologic slices. The distances from the arterialwall can be seen at different locations and generally range from 0.3 mmto 10 mm. Nonetheless, these images are from actual renal arteries andnerves and are used so as to develop the treatment plan for the system.For example, once the arterial wall is localized 9730 using the Doppleror other ultrasound signal, a model of the position of the nerves can beestablished and the energy then targeted to that region to inhibit theactivity of the nerves 9720. Notably, the distance of many of thesenerves from the wall of the blood vessel indicate that a therapy whichapplies radiofrequency to the wall of the vessel from the inside of thevessel likely has great difficulty in reaching a majority of the nervesaround the blood vessel wall.

FIG. 29D depicts a schematic from a live human ultrasound. As can beseen, the ultrasound travels through skin, through the subcutaneous fat,through the muscle and at least partially through the kidney 8935 toreach the hilum 8941 of the kidney and the renal blood vessels 8937.This direction was optimized through clinical experimentation so as tonot include structures which tend to scatter ultrasound such as bone andlung. Experimentation lead to the optimization of this position for theimaging and therapy of the renal nerves. The position of the ultrasoundis between the palpable bony landmarks on the posterior of the patientas described above and below. The vertebrae are medial, the ribssuperior and the iliac crest inferior. Importantly, the distance ofthese structures 8943 is approximately 8-12 cm and not prohibitive froma technical standpoint. These images from the ultrasound are thereforeconsistent with the results from the CT scans described above as well.

FIG. 29E depicts the surface area 8760 available to an ultrasoundtransducer for two patients out of a clinical study. One patient wasobese and the other thinner. Quantification of this surface area 8762was obtained by the following methodology: 1) obtain CT scan; 2) markoff boundary of organs such as the vertebrae, iliac crest, and ribs; 3)draw line from renal blood vessels to the point along the edge of thebone; 4) draw perpendicular from edge bone to the surface of the skin;5) map the collection of points obtained along the border of the bone.The surface area is the surface area between the points and the maximumdiameter is the greatest distance between the bony borders. Thecollection of points obtained with this method delimits the area on theposterior of the patient which is available to the ultrasound transducerto either visualize or treat the region of the focal spot. By studying aseries of patients, the range of surface areas was determined so as toassist in the design which will serve the majority of patients. Thetransducers modeled in FIG. 30 have surface areas of approximately 11×8cm or 88 cm² which is well within the surface area shown in FIG. 29E8762 which is representative of a patient series. Further more thelength, or distance, from the renal artery to the skin was quantified inshortest ray 8764 and longest ray 8766. Along with the angular datapresented above, these data enable design of an appropriate transducerto achieve autonomic modulation and control of blood pressure.

In a separate study, it was shown that these nerves could be inhibitedusing ultrasound applied externally with the parameters and devicesdescribed herein. Pathologic analysis revealed that the nerves aroundthe artery were completely inhibited and degenerated, confirming theability of the treatment plan to inhibit these nerves and ultimately totreat diseases such as hypertension. Furthermore, utilizing theseparameters, did not cause any damage within the path of the ultrasoundthrough the kidney and to the renal hilum.

Importantly, it has also been discovered via clinical trials that whenultrasound is used as the energy applied externally, that centering thediagnostic ultrasound probe such that a cross section of the kidney isvisualized and the vessels are visualized, is an important component ofdelivering the therapy to the correct position along the blood vessels.One of the first steps in the algorithm 9700 is to stabilize the patientin a patient stabilizer custom built to deliver energy to the region ofthe renal arteries. After stabilization of the patient, diagnosticultrasound is applied to the region 9730 to establish the extent of theribs, vertebrae, and pelvis location. Palpation of the bony landmarksalso allows for the demarcation of the treatment zone of interest. Theexternal ultrasound system is then placed within these regions so as toavoid bone. Then, by ensuring that a portion of the external energy isdelivered across the kidney (for example, using ultrasound forvisualization), the possibility of hitting bowel is all but eliminated.The ultrasound image in FIG. 29D depicts a soft tissue path from outsidethe patient to the renal hilum inside the patient. The distance isapproximately 8-16 cm. Once the patient is positioned, a cushion 9815 isplaced under the patient. In one embodiment, the cushion 9815 is simplya way to prop up the back of the patient. In another embodiment, thecushion 9815 is an expandable device in which expansion of the device isadjustable for the individual patient. The expandable component 9815allows for compression of the retroperitoneum (where the kidney resides)to slow down or dampen movement of the kidney and maintain its positionfor treatment with the energy source or ultrasound.

A test dose of energy 9740 can be given to the region of the kidneyhilum or renal artery and temperature imaging 9735, constriction ofblood vessels 9755, CT scans 9760, microneurography 9765 patch orelectrode, and even blood pressure 9770. Thereafter, the treatment canbe completed 9745. Completion might occur minutes, hours, days, or yearslater depending on the parameter being measured.

Through experimentation, it has been determined that the region of therenal hilum and kidneys can be stabilized utilizing gravity with localapplication of force to the region of the abdomen below the ribs andabove the renal pelvis. For example, FIGS. 28A-C depict examples ofpatient positioners intended to treat the region of the renal bloodvessels.

FIG. 28A is one example of a patient positioned in which the ultrasounddiagnostic and therapeutic 9820 is placed underneath the patient. Thepositioner 9810 is in the form of a tiltable bed. A patient elevator9815 placed under the patient pushes the renal hilum closer to the skinand can be pushed forward in this manner; as determined in clinicaltrials, the renal artery is approximately 2-3 cm more superficial inthis type of arrangement with a range of approximately 7-15 cm in thepatients studied within the clinical trial. The weight of the patientallows for some stabilization of the respiratory motion which wouldotherwise occur; the patient elevator can be localized to one side oranother depending on the region to be treated.

FIG. 28B detects a more detailed configuration of the ultrasound imagingand therapy engine 9820 inset. A patient interface 9815 is utilized tocreate a smooth transition for the ultrasound waves to travel throughthe skin and to the kidneys for treatment. The interface is adjustablesuch that it is customizable for each patient.

FIG. 28C depicts another embodiment of a positioner device 9850, thistime meant for the patient to be face down. In this embodiment, thepatient is positioned in the prone position lying over the patientelevator 9815. Again, through clinical experimentation, it wasdetermined that the prone position with the positioner under the patientpushes the renal hilum posterior and stretches out the renal artery andvein allowing them to be more visible to ultrasound and accessible toenergy deposition in the region. The positioner underneath the patientmight be an expandable bladder with one or more compartments whichallows for adjustability in the amount of pressure applied to theunderside of the patient. The positioner might also have a back sidewhich is expandable 9825 and can push against the posterior side of thepatient toward the expandable front side of the positioner therebycompressing the stretched out renal blood vessels to allow for a moresuperficial and easier application of the energy device. These data canbe seen in FIGS. 7G and 7H where the renal artery is quite a bit closerto the skin (7-17 cm down to 6-10 cm). The position of the energydevices for the left side 9827 of the patient and right side 9828 of thepatient are depicted in FIG. 28C. The ribs 9829 delimit the upper regionof the device placement and the iliac crest 9831 delimits the lowerregion of the device placement. The spinous processes 9832 delimit themedial edge of the region where the device can be placed and the regionbetween 9828 is the location where the therapeutic transducer is placed.

The table elevation is on the front side of the patient, pushing upwardtoward the renal hilum and kidneys. The head of the table may be droppedor elevated so as to allow specific positioning positions. The elevatedportion may contain an inflateable structure which controllably appliespressure to one side or another of the torso, head, or pelvis of thepatient.

FIG. 29A-C depicts the anatomical basis 9900 of the targeting approachdescribed herein. These figures are derived directly from histologicslides. Nerves 9910 can be seen in a position around renal artery 9920.The range of radial distance from the artery is out to 2 mm and even outto 10 mm. Anatomic correlation with the modeling in FIG. 16B reveals thefeasibility of the targeting and validates the approach based on actualpathology; that is, the approach of applying therapy to the renal nervesby targeting the adventitia of the artery. This is important because themethodology used to target the nerves is one of detecting the Dopplersignal from the artery and then targeting the vessel wall around thedoppler signal. Nerves 9910 can be seen surrounding the renal artery9920 which puts them squarely into the temperature field shown in 16Bindicating the feasibility of the outlined targeting approach in FIG. 27and the lesion configuration in FIG. 16A. Further experimentation(utilizing similar types of pathology as well as levels ofnorepinephrine in the kidney) reveals that the required dose ofultrasound to the region to affect changes in the nerves is on the orderof 100 W/cm² for partial inhibition of the nerves and 1-2 kW/cm² forcomplete inhibition and necrosis of the nerves. These doses or doses inbetween them might be chosen depending on the degree of nerve inhibitiondesired in the treatment plan. Importantly, it was further discoveredthrough the experimentation that an acoustic plane through the bloodvessels was adequate to partially or completely inhibit the nerves inthe region. That is to say, that a plane through which the blood vesselstravels perpendicularly is adequate to ablate the nerves around theartery as illustrated in FIG. 16B. Until this experimentation, there hadbeen no evidence that ultrasound would be able to inhibit nervessurrounding an artery by applying a plane of ultrasound through theblood vessel. Indeed, it was proven that a plane of ultrasoundessentially could circumferentially inhibit the nerves around the bloodvessel.

FIGS. 30A-I depict three dimensional simulations from a set of CT scansfrom the patient model shown in FIG. 26A. Numerical simulations wereperformed in three dimensions with actual human anatomy from the CTscans. The same CT scans utilized to produce FIGS. 7E, 19, and 25 wereutilized to simulate a theoretical treatment of the renal artery regionconsidering the anatomy of a real patient. Utilizing the doses shown inthe experimentation above (FIGS. 29A-D) combined with the human anatomyfrom the CT scans, it is shown with these simulations that the abilityexists to apply therapeutic ultrasound to the renal hilum from aposition outside the patient. In combination with FIG. 29, which asdiscussed, depicts the position of the nerves around the blood vesselsas well as the position of the vessels in an ultrasound, FIG. 30A-Idepicts the feasibility of an ultrasound transducer which is configuredto apply the required energy to the region of the hilum of the kidneywithout damaging intervening structures. These simulations are in factconfirmation for the proof of concept for this therapy and incorporatethe knowledge obtained from the pathology, human CT scans, humanultrasound scans, and the system designs presented previously above.

In one embodiment, FIG. 30A, the maximum intensity is reached at thefocus 10010 is approximately 186 W/cm² with a transducer 10000 design at750 MHz; the transducer is approximately 11×8 cm with a central portion10050 for an ultrasound imaging engine. The input wattage to thetransducer is approximately 120 W-150 W depending on the specificpatient anatomy.

FIGS. 30B and 30C depict the acoustic focus 10020, 10030 at a depth ofapproximately 9-11 cm and in two dimensions. Importantly, the region(tissues such as kidney, ureter, skin, muscle) proximal (10040 and10041) to the focus 10020, 10030 do not have any significant acousticpower absorption indicating that the treatment can be applied safely tothe renal artery region through these tissues as described above.Importantly, the intervening tissues are not injured in this simulationindicating the feasibility of this treatment paradigm.

FIGS. 30D-F depict a simulation with a transducer 10055 having afrequency of approximately 1 MHz. With this frequency, the focal spot10070, 10040, 10050 size is a bit smaller (approximately 2 cm by 0.5 cm)and the maximum power higher at the focus, approximately 400 W/cm² thanshown in FIGS. 30A-C. In the human simulation, this is close to anoptimal response and dictates the design parameters for the externallyplaced devices. The transducer in this design is a rectangular type ofdesign (spherical with the edges shaved off) so as to optimize theworking space in between the posterior ribs of the patient and thesuperior portion of the iliac crest of the patient. Its size isapproximately 11 cm×8 cm which as described above and below is wellwithin the space between the bony landmarks of the back of the patient.

FIGS. 30G-I depict a simulation with similar ultrasound variables asseen in FIGS. 30D-F. The difference is that the transducer 10090 wasleft as spherical with a central cutout rather than rectangular with acentral cutout. The spherical transducer setup 10090 allows for agreater concentration of energy at the focus 1075 due to the increasedsurface area of vibratory energy. Indeed, the maximum energy from thistransducer (FIG. 30G) is approximately 744 W/cm² whereas for thetransducer in FIG. 30 d, the maximum intensity is approximately 370W/cm². FIG. 30H depicts one plane of the model and 30I another plane.Focus 10080, 10085 is depicted with intervening regions 10082 and 10083free from acoustic power and heat generation, similar to FIG. 30A-F.

These simulations confirm the feasibility of a therapeutic treatment ofthe renal sympathetic nerves from the outside without damage tointervening tissues or structures such as bone, bowel, and lung.Hypertension is one clinical application of this therapy. A transducerwith an imaging unit within is utilized to apply focused ultrasound to arenal nerve surrounding a renal artery. Both the afferent nerves andefferent nerves are affected by this therapy.

Other transducer configurations are possible. Although a singletherapeutic transducer is shown in FIG. 30A-I, configurations such asphased array therapy transducers (more than one independently controlledtherapeutic transducer) are possible. Such transducers allow morespecific tailoring to the individual patient. For example, a largertransducer might be utilized with 2, 3, 4 or greater than 4 transducers.Individual transducers might be turned on or off depending on thepatients anatomy. For example, a transducer which would cover a rib inan individual patient might be turned off during the therapy.

Although the central space is shown in the center of the transducer inFIGS. 30A-I, the imaging transducer might be placed anywhere within thefield as long as its position is well known relative to the therapytransducers. For example, insofar as the transducer for therapy iscoupled to the imaging transducer spatially in three dimensional spaceand this relationship is always known, the imaging transducer can be inany orientation relative to the therapeutic transducer.

1. A system to modulate an autonomic nerve in a patient utilizingtranscutaneous ultrasound energy delivery, the system comprising: aprocessor comprising: an input for receiving information regardingenergy and power to be delivered to a treatment region containing thenerve; and an output for outputting a signal; wherein the processor isconfigured to determine a position of a reference target from outsidethe patient to localize the nerve relative to the reference target; atherapeutic energy device comprising: a transducer for deliveringultrasound energy from outside the patient; a controller to control anaiming of the transducer based at least in part on the signal from theprocessor; and an imaging system coupled to the processor or thetherapeutic energy device.
 2. The system of claim 1, wherein theprocessor is configured to determine the position during an operation ofthe therapeutic energy device.
 3. The system of claim 1, furthercomprising a patient interface configured to position the therapeuticdevice so that the transducer is aimed toward a blood vessel connectedto a kidney from a position between ribs superiorly, a iliac crestinferiorly, and a vertebral column medially.
 4. The system of claim 1,wherein the therapeutic energy device is configured to deliver focusedultrasound.
 5. The system of claim 1, wherein the reference target is atleast a portion of a blood vessel traveling to or from a kidney, and thenerve is a renal nerve.
 6. The system of claim 5, wherein the transduceris configured to focus the ultrasound energy at a distance from 6 cm to18 cm.
 7. The system of claim 1, wherein the transducer is configured todeliver the ultrasound energy to a renal blood vessel at an angleranging between about −10 degrees and about −48 degrees relative to ahorizontal line connecting transverse processes of a spinal column. 8.The system of claim 1, wherein the ultrasound energy from thetherapeutic energy device ranges between 100 W/cm2 and 2500 W/cm2. 9.The system of claim 1, wherein the reference target is an indwellingvascular catheter.
 10. The system of claim 1, wherein the imaging systemis a magnetic resonance imaging system.
 11. The system of claim 1,wherein the imaging system is an ultrasound imaging system.
 12. Thesystem of claim 1, wherein the processor is a part of the therapeuticenergy device.
 13. The system of claim 1, wherein the processor is apart of the imaging system.
 14. A system to inhibit a function of anerve surrounding a renal artery comprising: a detector to detect apositional signal indicative of a location of the renal artery from aposition external to a patient; an ultrasound component to delivertherapeutic energy through a skin of the patient to the nervesurrounding the renal artery; and a processing unit configured to:obtain information regarding a three dimensional coordinate spacecontaining the ultrasound component, obtain the location of the renalartery, and determine a direction and an energy level for thetherapeutic energy based on the information and the location of therenal artery.
 15. The system of claim 14, further comprising anintravascular catheter configured to communicate with the detector. 16.The system of claim 15, wherein the intravascular catheter is configuredto provide the position signal for detection by the detector.
 17. Thesystem of claim 14, wherein the processing unit is configured forfocusing the therapeutic energy on two sides of the renal artery. 18.The system of claim 14, wherein the processing unit is configured toprovide an output to instruct the ultrasound component to create alesion in which a major axis of the lesion is along a longitudinallength of the renal artery.
 19. The system of claim 18, wherein theprocessing unit is configured to provide the output to instruct theultrasound component to deliver multiple lesions around the renal arterysimultaneously.
 20. The system of claim 14, wherein the processing unitis configured to provide an output to instruct the ultrasound componentto create a circumferential lesion around the renal artery.
 21. Thesystem of claim 18, wherein the lesion is around the renal artery justproximal to a bifurcation of the renal artery.
 22. The system of claim14, further comprising a fiducial, locatable from a position outside thepatient, adapted to be temporarily placed in the artery of the patient,and to communicate with the detector to provide the indication of thelocation of the renal artery in a three dimensional reference frame. 23.A method to stimulate or inhibit the function of a nerve traveling to orfrom the kidney comprising: identifying an acoustic window at theposterior region of a patient in which renal arteries can be visualized;transmitting a first energy through a skin of the patient from theposterior region of the patient; imaging an arterial region using thefirst transmitted energy; and applying a second transmitted energy to anarterial adventitia based on the imaged arterial region.
 24. The methodof claim 23, wherein the act of imaging is performed repeatedly to trackthe arterial region.
 25. A method to locate a position of a blood vesselin a body of a patient comprising: applying a first wave of ultrasound,from a first direction, to a region of a blood vessel from outside ofthe patient, and detecting its return signal; comparing the appliedfirst wave and its return signal; simultaneously, or sequentially,applying a second wave of ultrasound from a second direction to theblood vessel, and detecting a its return signal; and integrating thereturn signal from the first wave and the return signal from the secondwave to determine the position, in a three dimensional coordinatereference, of the blood vessel.
 26. The method of claim 25, furthercomprising instructing a therapeutic ultrasound transducer to applyenergy to the position of the blood vessel.